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In JoVE (1)
Other Publications (199)
- IEEE Transactions on Bio-medical Engineering
- Scottish Medical Journal
- Nucleic Acids Research
- Diseases of the Esophagus : Official Journal of the International Society for Diseases of the Esophagus / I.S.D.E
- The Journal of Hand Surgery
- Antimicrobial Agents and Chemotherapy
- Journal of the American Dietetic Association
- Clinical Orthopaedics and Related Research
- Journal of the American College of Cardiology
- Investigative Ophthalmology & Visual Science
- The Practitioner
- Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine
- FEBS Letters
- FEBS Letters
- Chinese Medical Journal
- IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society
- Molecular Vision
- Cancer Research
- Journal of Structural Biology
- The American Journal of Tropical Medicine and Hygiene
- Toxicological Sciences : an Official Journal of the Society of Toxicology
- American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists
- Bioinformatics (Oxford, England)
- Science (New York, N.Y.)
- American Journal of Infection Control
- American Journal of Preventive Medicine
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Applied Clinical Medical Physics / American College of Medical Physics
- Nature Reviews. Cancer
- Regulatory Toxicology and Pharmacology : RTP
- Journal of Refractive Surgery (Thorofare, N.J. : 1995)
- Journal of Environmental Management
- Investigative Ophthalmology & Visual Science
- Techniques in Hand & Upper Extremity Surgery
- Cochrane Database of Systematic Reviews (Online)
- FEBS Letters
- Journal of the American Chemical Society
- Cell Cycle (Georgetown, Tex.)
- Journal of Orthopaedic Trauma
- Current Eye Research
- Progress in Retinal and Eye Research
- Muscle & Nerve
- Environmental Health Perspectives
- Emergency Medicine Australasia : EMA
- Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery / Nordisk Plastikkirurgisk Forening [and] Nordisk Klubb for Handkirurgi
- Ecological Applications : a Publication of the Ecological Society of America
- The American Journal of Gastroenterology
- The Journal of Experimental Biology
- The Journal of Biological Chemistry
- Cold Spring Harbor Perspectives in Biology
- Bioinformatics (Oxford, England)
- The Journal of Pediatrics
- The Pediatric Infectious Disease Journal
- American Journal of Respiratory and Critical Care Medicine
- European Journal of Immunology
- Breastfeeding Medicine : the Official Journal of the Academy of Breastfeeding Medicine
- Progress in Neurobiology
- Journal of the American Chemical Society
- Cell Cycle (Georgetown, Tex.)
- Current Eye Research
- American Journal of Human Genetics
- The EMBO Journal
- The Journal of Infectious Diseases
- The Journal of Bone and Joint Surgery. British Volume
- Cancer Research
- Emergency Medicine Australasia : EMA
- Acta Orthopaedica
- Journal of Environmental Quality
- Emergency Medicine Australasia : EMA
- PloS One
- Journal of Toxicology and Environmental Health. Part B, Critical Reviews
- Proceedings of the Institution of Mechanical Engineers. Part H, Journal of Engineering in Medicine
- Drug, Healthcare and Patient Safety
- The Journal of Arthroplasty
- Angewandte Chemie (International Ed. in English)
- Biochimica Et Biophysica Acta
- Journal of Structural Biology
- Cellular Signalling
- DNA Repair
- Seminars in Cancer Biology
- Journal of Thrombosis and Thrombolysis
- Investigative Ophthalmology & Visual Science
- Clinical Nutrition (Edinburgh, Scotland)
- European Journal of Pain (London, England)
- Journal of Toxicology and Environmental Health. Part A
- Journal of Toxicology and Environmental Health. Part A
- Investigative Ophthalmology & Visual Science
- Annals of Emergency Medicine
- Chemico-biological Interactions
- International Journal of Obesity (2005)
- Structure (London, England : 1993)
- The Journal of Infectious Diseases
- Antimicrobial Agents and Chemotherapy
- International Journal of Immunopathology and Pharmacology
- Antimicrobial Agents and Chemotherapy
- Journal of the Royal Society, Interface / the Royal Society
- Eye (London, England)
- The British Journal of Ophthalmology
- Computer Methods in Biomechanics and Biomedical Engineering
- The Journal of Bone and Joint Surgery. British Volume
- Biophysical Journal
- Investigative Ophthalmology & Visual Science
- Journal of Medical Case Reports
- PloS One
- The Journal of Bone and Joint Surgery. British Volume
- Molecular and Cellular Biochemistry
- Physical Chemistry Chemical Physics : PCCP
- The Journal of Antimicrobial Chemotherapy
- Experimental Physiology
- Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation
- Diabetes Care
- PloS One
- Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association
- IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society
- Antimicrobial Agents and Chemotherapy
- Current Biology : CB
- Hip International : the Journal of Clinical and Experimental Research on Hip Pathology and Therapy
- Molecular and Cellular Biology
- The EMBO Journal
- BMC Immunology
- Journal of Adolescence
- Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry
- Mutation Research
- Clinical Rehabilitation
- IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society
- Behavior Research Methods
- Journal of Pain and Symptom Management
- Acta Ophthalmologica
- Lancet Neurology
- Regulatory Toxicology and Pharmacology : RTP
- Emergency Medicine Australasia : EMA
- American Journal of Obstetrics and Gynecology
- Infectious Diseases in Obstetrics and Gynecology
- Clinical Chemistry
- Nursing Administration Quarterly
- American Journal of Infection Control
- The Journal of Experimental Biology
- Journal of Cataract and Refractive Surgery
- Behavior Genetics
- The Journal of Bone and Joint Surgery. British Volume
- Archives of Orthopaedic and Trauma Surgery
- Critical Reviews in Toxicology
- International Journal of Clinical Practice
- Tropical Medicine & International Health : TM & IH
- Investigative Ophthalmology & Visual Science
- Journal of Pain and Symptom Management
- Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Für Klinische Und Experimentelle Ophthalmologie
- Advanced Materials (Deerfield Beach, Fla.)
- Digestive Diseases and Sciences
- The Review of Scientific Instruments
- Emerging Infectious Diseases
- Malaria Journal
- The Journal of Infectious Diseases
- The EMBO Journal
- JEMS : a Journal of Emergency Medical Services
- Techniques in Vascular and Interventional Radiology
- Veterinary Microbiology
- Journal of Opioid Management
- Nursing New Zealand (Wellington, N.Z. : 1995)
- Nucleic Acids Research
- Journal of Long-term Effects of Medical Implants
- Molecular Vision
- Journal of Plastic Surgery and Hand Surgery
- Journal of Plastic Surgery and Hand Surgery
- Current Medical Research and Opinion
- Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society
- Chronic Respiratory Disease
- Archives of Ophthalmology
- American Journal of Respiratory and Critical Care Medicine
- Nucleic Acids Research
- Toxicological Sciences : an Official Journal of the Society of Toxicology
- The Journal of Arthroplasty
- Antimicrobial Agents and Chemotherapy
- The Journal of Infectious Diseases
- Professional Case Management
- Archives of Disease in Childhood. Education and Practice Edition
- Movement Disorders : Official Journal of the Movement Disorder Society
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Articles by J. Meek in JoVE
מדידות אלקטרו וניתוח Nociception אצל תינוקות אדם
L. Fabrizi*1, A. Worley*2, D. Patten1, S. Holdridge1, L. Cornelissen1, J. Meek3, S. Boyd2, R. Slater1,4
1Neuroscience, Physiology and Pharmacology, University College London, 2Department of Clinical Neurophysiology, Great Ormond Street Hospital, 3Elizabeth Garrett Anderson Obstetric Hospital, University College Hospital, 4Nuffield Department of Anaesthetics, University of Oxford
הערכה וטיפול של כאב אצל תינוקות קשה בגלל שתינוקות לא יכולים לדווח מילולית הניסיון שלהם. בסרט זה אנו מתארים שיטות אלקטרו כמותיים וטכניקות ניתוח זה יכול לשמש כדי למדוד את התגובה לאירועים הרעילים ממערכת העצבים התינוק.
Other articles by J. Meek on PubMed
IEEE Transactions on Bio-medical Engineering. Jun, 2008 | Pubmed ID: 19272956
Sensitivity of applied grasp force is improved for a myoelectrically controlled prosthetic hand under force control through normal force derivative feedback. Benchtop experiments and results from twelve human test subjects indicate that normal force derivative feedback can be used in prosthetic hands to help prevent accidental damage to delicate objects.
Scottish Medical Journal. Feb, 2009 | Pubmed ID: 19291928
With increased use of the internet for health information and direct to consumer advertising from medical companies, there is concern about the quality of information available to patients. The aim of this study was to examine the quality of health information on the internet for hip resurfacing.
Nucleic Acids Research. May, 2009 | Pubmed ID: 19295133
Here we define an important role for heat shock factor 1 (HSF1) in the cellular response to genotoxic agents. We demonstrate for the first time that HSF1 can complex with nuclear p53 and that both proteins are co-operatively recruited to p53-responsive genes such as p21. Analysis of natural and synthetic cis elements demonstrates that HSF1 can enhance p53-mediated transcription, whilst depletion of HSF1 reduces the expression of p53-responsive transcripts. We find that HSF1 is required for optimal p21 expression and p53-mediated cell-cycle arrest in response to genotoxins while loss of HSF1 attenuates apoptosis in response to these agents. To explain these novel properties of HSF1 we show that HSF1 can complex with DNA damage kinases ATR and Chk1 to effect p53 phosphorylation in response to DNA damage. Our data reveal HSF1 as a key transcriptional regulator in response to genotoxic compounds widely used in the clinical setting, and suggest that HSF1 will contribute to the efficacy of these agents.
Diseases of the Esophagus : Official Journal of the International Society for Diseases of the Esophagus / I.S.D.E. 2009 | Pubmed ID: 19302213
Greater than 50% of patients with esophageal carcinoma are found to be incurable at the time of diagnosis, leaving only palliative options. Self-expanding metal stents (SEMs) are effective for relieving symptoms and complications associated with esophageal carcinoma and improving quality of life. We undertook a retrospective analysis to evaluate the experience of palliative esophageal stenting for symptomatic malignant dysphagia in our institution over a period of 7 years. Between January 1999 and January 2006, 126 patients who received SEMs for malignant dysphagia were identified using an upper gastrointestinal specialist nurse clinician database. Data were obtained from patient case notes, endoscopy, histopathology, radiology, and external agency databases. Of the 126 identified, 36 patients were excluded from the analysis. A number of variables including age, sex, presenting complaints, type of stent, indications of stenting, success or failure of stent insertion, survival rate, and complication rate were analyzed. Of the 90 patients, 55 (61%) were male and 35 (39%) were female. The mean age of patients was 70.79 (range 40-97) years. The predominant presenting complaints were dysphagia (n = 81) and weight loss (n = 48). The indication for stenting was worsening dysphagia in all patients. Tumors were confined to the distal esophagus and esophagogastric junction in 73 patients (81%), and the mid-esophagus in 17 (19%). Adenocarcinoma was identified in 61 patients (67.8%) and squamous cell carcinoma in 29 (32.2%). Stenting numbers were comparable in endoscopic and radiologic groups (47 vs. 43), with successful stent deployment in 89 patients. The 7- and 30-day mortality was 9% (n = 8) and 28% (n = 25), respectively. Comparable numbers of early deaths were seen in both radiologic (n = 13) and endoscopic (n = 12) groups. Causes of early inpatient death included hemorrhage (n = 5), pneumonia (n = 7), exhaustion (n = 2), cardiac causes (n = 3), perforation (n = 1), and sepsis (n = 1). The number of patients with complications was 41 (45.6%), 25 in the surgical group and 15 in the radiologic group; the difference was not significant (P = 0.13). The mean survival time was 92.5 (0-638) days and median survival time was 61 days. A subgroup of patients with complete dysphagia (score 4) gained a mean survival of 59 days. Those patients receiving adjuvant chemotherapy or radiotherapy survived significantly longer than those receiving stenting alone (152.8 days vs. 71.8 days). There is no significant difference in complications or survival when using endoscopic or radiologic methods to deploy SEMs in patients with inoperable esophageal cancer. Mortality is low; however, the morbidity rate is significant. Patients receiving adjuvant chemotherapy or radiotherapy, in addition to stenting, survived significantly longer than those with a stent only.
Nature. May, 2009 | Pubmed ID: 19424137
Treatment of a Little Finger Synovial Cyst by Repair of an Opening in the Wrist Capsule: Case Report
The Journal of Hand Surgery. Jul-Aug, 2009 | Pubmed ID: 19442456
As synovial fluid from the wrist may leak into the ulnar bursa and from there into the flexor synovial sheath in the little finger, the origin of a synovial cyst of the pulp of the little finger may be in the wrist. Here we present the surgical treatment of a patient with a synovial cyst of the pulp of the little finger by surgery of the wrist and palm of the hand after failed conservative treatment.
Pharmacokinetics-pharmacodynamics of Pyrazinamide in a Novel in Vitro Model of Tuberculosis for Sterilizing Effect: a Paradigm for Faster Assessment of New Antituberculosis Drugs
Antimicrobial Agents and Chemotherapy. Aug, 2009 | Pubmed ID: 19451303
There are currently renewed efforts to develop drugs that could shorten the duration of antituberculosis therapy. This is best achieved by optimizing the sterilizing effect. However, the current pathway for the development of new molecules with the potential to have a sterilizing effect is inefficient. We designed an in vitro pharmacokinetic-pharmacodynamic model in which Mycobacterium tuberculosis replicating slowly at pH 5.8 was exposed to pyrazinamide by use of the concentration-time profiles encountered in patients. The sterilizing effect rates and the time to the emergence of drug resistance were examined. Daily pyrazinamide dosing for 28 days accurately achieved (i) the pyrazinamide pharmacokinetic parameters, (ii) the lack of early bactericidal activity, (iii) a sterilizing effect rate of 0.10 log(10) CFU/ml per day starting on day 6 of therapy, and (iv) a time to the emergence of resistance of the from 2 to 3 weeks of monotherapy encountered in patients with tuberculosis. Next, dose-scheduling studies were performed. The sterilizing effect was linked to the pyrazinamide ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC (r(2) = 0.80 to 0.90), with 90% of the maximal effect being achieved by an AUC(0-24)/MIC of 209.08. Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (r(2) = 0.73 to 0.91). Monte Carlo simulations of 10,000 patients demonstrated that the currently recommended pyrazinamide doses (15 to 30 mg/kg of body weight/day) achieved the AUC(0-24)/MIC of 209.08 in the epithelial lining fluid of only 15.1 to 53.3% of patients. Doses of >60 mg/kg per day performed better. Our vitro model for the sterilizing effect, together with Monte Carlo simulations, can be used for the faster identification of the clinical doses that are needed to achieve a sterilizing effect and that can then be studied in clinical trials.
Journal of the American Dietetic Association. Jun, 2009 | Pubmed ID: 19465175
Clinical Orthopaedics and Related Research. Nov, 2009 | Pubmed ID: 19565304
The increase in metal-on-metal hip arthroplasties has led to concern regarding the effect of raised serum and tissue metal ion levels. Our aim was to determine changes in the integrity and function of cells of the immune system after exposure to CoCr nanoparticles in specific cell culture experiments. Nanometer-sized particles of CoCr were made from a manufacturer's forged CoCr used for metal-on-metal articulations. Primary, murine dendritic cells and T and B lymphocytes then were exposed to these CoCr particles under cell culture conditions and then assayed for viability and proliferation/activation. CoCr nanoparticles did not directly activate dendritic cells or regulate B cells. Although nanoparticles were not directly toxic to resting T cells, Signals 1- and 2-dependent T cell proliferation were reduced. This may explain the observed reduction in CD8+ T cells observed in patients with metal-on-metal implants.
Microsurgery. 2009 | Pubmed ID: 19308952
One way to improve nerve regeneration and bridge longer nerve gaps may be the use of semipermeable/porous conduits. With porosity less biomaterial is used for the nerve conduit. We evaluated the short-term effects of porous Neurolac nerve conduits for in vivo peripheral nerve regeneration. In 10 male Black Hooded rats, a gap of 10 mm was bridged by a porous Neurolac nerve conduit. Evaluation point ranged from 3 to 12 weeks. The sciatic nerve function was not measurable due to automutilation and flexion contractures. The gait-stance duration showed no improvement with time, indicating a disturbed walking pattern. The nerve guides showed very fast degradation with swelling, fragmentation, and collapse. Furthermore, a severe foreign body reaction occurred. Nerve regeneration was severely hampered. This study showed no beneficial effects of porous Neurolac nerve conduits when compared with previous findings with nonporous copolymeric nerve guides of a slightly different composition.
Edema As a Very Early Marker for Acute Myocardial Ischemia: a Cardiovascular Magnetic Resonance Study
Journal of the American College of Cardiology. Apr, 2009 | Pubmed ID: 19341860
This study was designed to determine whether imaging myocardial edema would identify acute myocardial ischemia before irreversible injury takes place.
Stromal Edema in Klf4 Conditional Null Mouse Cornea is Associated with Altered Collagen Fibril Organization and Reduced Proteoglycans
Investigative Ophthalmology & Visual Science. Sep, 2009 | Pubmed ID: 19387067
Klf4, one of the highly expressed transcription factors in the mouse cornea, plays an important role in maturation and maintenance of the ocular surface. In this study, the structure and proteoglycan composition of the Klf4 conditional null (Klf4CN) corneal stroma was investigated, to further characterize the previously reported Klf4CN stromal edema.
The Practitioner. Nov, 2009 | Pubmed ID: 20043505
In OSA, the patient suffers repeated episodes of apnoea caused by narrowing or closure of the pharyngeal airway during sleep. The degree of closure of the airway leads to periods of either apnoea (complete) or hypopnoea (partial) obstruction. Population-based surveys estimate that 2-4% of the middle-aged population have OSA, which is similar to the prevalence of diabetes and asthma. Although understanding of the condition has improved considerably, it is estimated that 85-90% of sufferers still remain undiagnosed. OSA is not only a cause of excessive daytime somnolence leading to an increased risk of accidents on the road and poor work performance, but also a major cause of social dysfunction, reduced quality of life related to poor health, and mood disorders. Untreated OSA predicts a substantially increased risk of hypertension, cardiovascular disease, cerebrovascular disease, depression, and mortality. Wherever OSA is considered, the following questions should be asked: Is this patient falling asleep regularly against their will? Is this patient often sleepy while driving? Is this patient experiencing difficulty at work because of excessive sleepiness? Is sleep refreshing? Is surgery for snoring being considered (OSA should be excluded first)? The gold standard for investigation of OSA is polysomnography. It is possible to diagnose almost 90% of OSA patients from limited sleep studies often conducted on a domiciliary basis with portable diagnostic equipment.
Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. Dec, 2009 | Pubmed ID: 20053251
The objective was to describe the association between verbal descriptors of nausea severity and visual analog scale (VAS) ratings in an undifferentiated emergency department (ED) population and to calculate the minimum clinically significant difference (MCSD) in VAS rating of nausea severity in this population.
FEBS Letters. Feb, 2009 | Pubmed ID: 19166840
The p53 tumour suppressor protein is tightly controlled by the E3 ubiquitin ligase, mouse double minute 2 (MDM2), but maintains MDM2 expression as part of a negative feedback loop. We have identified the immunophilin, 25kDa FK506-binding protein (FKBP25), previously shown to be regulated by p53-mediated repression, as an MDM2-interacting partner. We show that FKBP25 stimulates auto-ubiquitylation and proteasomal degradation of MDM2, leading to the induction of p53. Depletion of FKBP25 by siRNA leads to increased levels of MDM2 and a corresponding reduction in p53 and p21 levels. These data are consistent with the idea that FKBP25 contributes to regulation of the p53-MDM2 negative feedback loop.
14-3-3 Binding to Pim-phosphorylated Ser166 and Ser186 of Human Mdm2--Potential Interplay with the PKB/Akt Pathway and P14(ARF)
FEBS Letters. Feb, 2009 | Pubmed ID: 19166854
Here we show that 14-3-3 proteins bind to Pim kinase-phosphorylated Ser166 and Ser186 on the human E3 ubiquitin ligase mouse double minute 2 (Mdm2), but not protein kinase B (PKB)/Akt-phosphorylated Ser166 and Ser188. Pim-mediated phosphorylation of Ser186 blocks phosphorylation of Ser188 by PKB, indicating potential interplay between the Pim and PKB signaling pathways in regulating Mdm2. In cells, expression of Pim kinases promoted phosphorylation of Ser166 and Ser186, interaction of Mdm2 with endogenous 14-3-3s and p14(ARF), and also increased the amount of Mdm2 protein by a mechanism that does not require Pim kinase activities. The implications of these findings for regulation of the p53 pathway, oncogenesis and drug discovery are discussed.
Chinese Medical Journal. Jan, 2009 | Pubmed ID: 19187649
Frozen or dried corneal grafts are commonly used for stromal transplantation such as lamellar keratoplasty (full or partial thickness), keratophakia, epikeratophakia. Structural properties are important for the final optical results of these surgeries but the effects of freezing/thawing and drying/rehydration on the properties of the stroma are known little compared with the corneal endothelium, mainly because of lack of non-invasive technique to evaluate the stromal structure. This study aimed to investigate the swelling and structural properties of the bovine corneal stroma following freezing or drying by X-ray diffraction which was a non-invasive technique and could give ultra-structural information in hydrated tissues.
IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. Feb, 2009 | Pubmed ID: 19211326
Open loop and force controllers are compared experimentally with three robust parallel force-velocity controllers that are developed for a prosthetic hand. Robust sliding mode, backstepping, and hybrid sliding mode-backstepping (HSMBS) parallel force-velocity controllers are tested by ten able-bodied subjects. Results obtained with a myoelectrically controlled prosthesis indicate that all three robust controllers offer a statistically significant improvement over linear hand prosthesis control schemes. The robust controllers enable the human operators to more easily manipulate a delicate object. Bench top experiments combined with quantitative and qualitative evaluations from ten test subjects reveal the HSMBS controller to be the best choice to improve control of powered prosthetic hands.
Molecular Vision. 2009 | Pubmed ID: 19234631
Structural changes are well known to occur in the cornea after injury. The aim of this study was to investigate collagen orientation changes in the cornea during a short-term wound healing process.
Cancer Research. Mar, 2009 | Pubmed ID: 19244120
The mechanisms by which cells accurately distinguish between DNA double-strand break (DSB) ends and telomeric DNA ends remain poorly defined. Recent investigations have revealed intriguing interactions between DNA repair and telomeres. We were the first to report a requirement for the nonhomologous end-joining (NHEJ) protein DNA-dependent protein kinase (DNA-PK) in the effective end-capping of mammalian telomeres. Here, we report our continued characterization of uncapped (as opposed to shortened) dysfunctional telomeres in cells deficient for the catalytic subunit of DNA-PK (DNA-PKcs) and shed light on their consequence. We present evidence in support of our model that uncapped telomeres in this repair-deficient background are inappropriately detected and processed as DSBs and thus participate not only in spontaneous telomere-telomere fusion but, importantly, also in ionizing radiation-induced telomere-DSB fusion events. We show that phosphorylation of DNA-PKcs itself (Thr-2609 cluster) is a critical event for proper telomere end-processing and that ligase IV (NHEJ) is required for uncapped telomere fusion. We also find uncapped telomeres in cells from the BALB/c mouse, which harbors two single-nucleotide polymorphisms that result in reduced DNA-PKcs abundance and activity, most markedly in mammary tissue, and are both radiosensitive and susceptible to radiogenic mammary cancer. Our results suggest mechanistic links between uncapped/dysfunctional telomeres in DNA-PKcs-deficient backgrounds, radiation-induced instability, and breast cancer. These studies provide the first direct evidence of genetic susceptibility and environmental insult interactions leading to a unique and ongoing form of genomic instability capable of driving carcinogenesis.
Journal of Structural Biology. May, 2009 | Pubmed ID: 19258040
In the cornea, the precise organisation of fibrillar collagen and associated proteoglycans comprising the stromal extracellular matrix plays a major role in governing tissue form and function. Recently, abnormal collagen alignment was noted in the misshapen corneas of mature chickens affected by the retinopathy, globe enlarged (rge) mutation. Here we further characterize corneal ultrastructural changes as the rge eye develops post-hatch. Wide-angle X-ray scattering disclosed alteration to dominant collagen lamellae directions in the rge chick cornea, compared to age-matched controls. These changes accompanied eye globe enlargement and corneal flattening in affected birds, manifesting as a progressive loss of circumferential collagen alignment in the peripheral cornea and limbus in birds older than 1 month. Collagen intermolecular separation was unchanged in rge. However, small-angle X-ray scattering results suggest collagen fibril separation and diameter increase more rapidly towards the corneal periphery in rge at 3 months post-hatch compared to controls, although central collagen fibril diameter was unchanged. By transmission electron microscopy utilising cuprolinic blue stain, the morphology and distribution of stromal proteoglycans were unaltered in rge corneas otherwise demonstrating abnormal collagen fibril organisation. From a numerical simulation of tissue mechanics, progressive remodelling of stromal collagen in rge during globe enlargement post-hatch appears to be related to the corneal morphometric changes presented by the disease.
Review: Provider Practice and User Behavior Interventions to Improve Prompt and Effective Treatment of Malaria: Do We Know What Works?
The American Journal of Tropical Medicine and Hygiene. Mar, 2009 | Pubmed ID: 19270276
Effective case management of uncomplicated malaria is a cornerstone of successful malaria control. With current calls for the global elimination of malaria, all strategies to control malaria need to reach the highest achievable level of effective implementation. A systematic literature review of all interventions to improve provider- and/or user-side behavior in the prompt and appropriate treatment of uncomplicated malaria (with appropriate evaluation design and Roll Back Malaria outcome indicators) found 23 studies for review. Only 16 studies targeted providers, nine in the public sector and seven in the private sector. Just four interventions were conducted at national scale. These data suggest that very little is known about what interventions work in improving prompt and effective treatment of malaria. In the context of scaling up effective malaria control and malaria elimination plans and in increasing access to artemisinin combination therapies (ACTs), increased research in this area is crucial.
Pragmatic Challenges for the Vision of Toxicity Testing in the 21st Century in a Regulatory Context: Another Ames Test? ...or a New Edition of "the Red Book"?
Toxicological Sciences : an Official Journal of the Society of Toxicology. Mar, 2009 | Pubmed ID: 19168570
Transparent and Reproducible Reports of Economic Evaluations of Clinical Pharmacy Services: a Goal for the Future?
American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists. Mar, 2009 | Pubmed ID: 19233988
Bioinformatics (Oxford, England). Jun, 2009 | Pubmed ID: 19477987
We develop an hidden Markov model (HMM)-based algorithm for computing exact parametric and non-parametric linkage scores in larger pedigrees than was possible before. The algorithm is applicable whenever there are chains of persons in the pedigree with no genetic measurements and with unknown affection status. The algorithm is based on shrinking the state space of the HMM considerably using such chains. In a two g-degree cousins pedigree the reduction drops the state space from being exponential in g to being linear in g. For a Finnish family in which two affected children suffer from a rare cold-inducing sweating syndrome, we were able to reduce the state space by more than five orders of magnitude from 2(50) to 2(32). In another pedigree of state-space size of 2(27), used for a study of pituitary adenoma, the state space reduced by a factor of 8.5 and consequently exact linkage scores can now be computed, rather than approximated. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Science (New York, N.Y.). Jun, 2009 | Pubmed ID: 19556505
Magnetic trapping of atoms on chips has recently become straightforward, but analogous trapping of molecules has proved to be challenging. We demonstrated trapping of carbon monoxide molecules above a chip using direct loading from a supersonic beam. Upon arrival above the chip, the molecules are confined in tubular electric field traps approximately 20 micrometers in diameter, centered 25 micrometers above the chip, that move with the molecular beam at a velocity of several hundred meters per second. An array of these miniaturized moving traps is brought to a standstill over a distance of only a few centimeters. After a certain holding time, the molecules are accelerated off the chip again for detection. This loading and detection methodology is applicable to a wide variety of polar molecules, enabling the creation of a gas-phase molecular laboratory on a chip.
Use of Atmospheric Non-thermal Plasma As a Disinfectant for Objects Contaminated with Methicillin-resistant Staphylococcus Aureus
American Journal of Infection Control. Nov, 2009 | Pubmed ID: 19559504
Health care-associated infections because of methicillin-resistant strains of Staphylococcus aureus (MRSA) are increasing worldwide despite current infection control measures. Novel methods for disinfection of MRSA would be useful.
American Journal of Preventive Medicine. Sep, 2009 | Pubmed ID: 19595558
Peridomestic Lyme disease-prevention initiatives promote personal protection, landscape modification, and chemical control.
SCID Dogs: Similar Transplant Potential but Distinct Intra-uterine Growth Defects and Premature Replicative Senescence Compared with SCID Mice
Journal of Immunology (Baltimore, Md. : 1950). Aug, 2009 | Pubmed ID: 19635917
We have previously described DNA-dependent protein kinase (DNA-PKcs) mutations in horses and dogs that result in deficits in V(D)J recombination, DNA repair, and SCID. In this paper, we document substantial developmental growth defects in DNA-PKcs-deficient dogs that are not apparent in SCID mice. Fibroblast cell strains derived from either fetal or adult SCID dogs proliferate poorly in culture and undergo premature replicative senescence, somewhat reminiscent of cells derived from Ku-deficient mice. A limited number of animals have been immune reconstituted (by bone marrow transplantation) so that they can be maintained in a normal environment for long periods. Several of these animals have developed conditions associated with premature ageing at 2-3 years of age, roughly 20% of their expected lifespan. These conditions include intestinal malabsorption and primary neural cell neoplasia. These results suggest that DNA-PKcs deficiency is not tolerated equally in all species, perhaps providing insight into why DNA-PKcs deficiency has not been observed in humans. Finally, this study demonstrates the feasibility of maintaining SCID dogs for extended periods of time and documents their utility for bone marrow transplantation studies and as hosts for the propagation of xenografts. In sum, SCID dogs may present researchers with new possibilities for the development of animal models of human disease.
Journal of Applied Clinical Medical Physics / American College of Medical Physics. 2009 | Pubmed ID: 19692969
Varian Medical Systems (Palo Alto, CA) has implemented the Monte Carlo electron dose calculation algorithm (eMC) in the Eclipse treatment planning system. Previous algorithms for electron treatment planning were limited in their calculation ability for small field depth doses and monitor units. An old rule of thumb to approximate the limiting cutout size for an electron field was determined by the lateral scatter equilibrium and approximated by E (MeV)/2.5 in centimeters of water. In this study we compared eMC calculations and measurements of depth doses, isodose distributions and monitor units for several different energy and small field cutout size combinations at different SSDs. Measurements were made using EBT film (International Specialty Products, Wayne, NJ) and a PinPoint Ion Chamber (PTW, Hicksville, NY). Our results indicate that the eMC algorithm can accurately predict depth doses, isodose distributions and monitor units (within 2.5%) for field sizes as small as 3.0 cm diameter for energies in the 6 to 20 MeV range at 100 cm SSD. Therefore, the previous energy dependent rule of thumb does not apply to the Eclipse electron Monte Carlo code. However, at extended SSDs (105-110 cm), the results show good agreement (within 4 %) only for higher energies (12, 16, and 20 MeV) for a field size of 3 cm.
Nature Reviews. Cancer. Oct, 2009 | Pubmed ID: 19730431
Loss of p53 function occurs during the development of most, if not all, tumour types. This paves the way for genomic instability, tumour-associated changes in metabolism, insensitivity to apoptotic signals, invasiveness and motility. However, the nature of the causal link between early tumorigenic events and the induction of the p53-mediated checkpoints that constitute a barrier to tumour progression remains uncertain. This Review considers the role of the DNA damage response, which is activated during the early stages of tumour development, in mobilizing the tumour suppression function of p53. The relationship between these events and oncogene-induced p53 activation through the ARF pathway is also discussed.
Tools for the Prioritization of Substances on the Domestic Substances List in Canada on the Basis of Hazard
Regulatory Toxicology and Pharmacology : RTP. Dec, 2009 | Pubmed ID: 19766685
A precedent setting legislative mandate under the Canadian Environmental Protection Act 1999 to establish priorities for assessment based on systematic consideration of all of the approximately 23,000 Existing Chemicals in Canada required the development and refinement of methodology in a number of important areas. This included development of simple and complex exposure and hazard tools for priority setting which draw maximally and efficiently on available data to systematically identify substances that are highest priorities in relation to their potential to cause adverse effects on the general population. The hierarchical approach in the simple and complex hazard tools described here efficiently and effectively sets substances aside as non-priorities, or prioritizes them for consideration additionally in assessment. The hazard tools efficiently incorporate previous work, contributing to consistency internationally, and involve hierarchical consideration of sources of information based on their relative weighting. They are health protective, based on their incorporated degree of conservatism, and provide direction for additional assessment for substances deemed to be priorities. Although designed for prioritization of Existing Substances in Canada, these tools have potential for broader application in other national and international programs to provide focus and increase efficiency in human health risk assessment.
Journal of Refractive Surgery (Thorofare, N.J. : 1995). Sep, 2009 | Pubmed ID: 19772262
To compare stromal riboflavin absorption after 20% alcohol application and partial or complete epithelial removal by analyzing light transmission properties of porcine corneas after riboflavin/ultraviolet A (UVA) corneal collagen cross-linking.
Limitations of an Optimum Sustainable Population or Potential Biological Removal Approach for Conserving Marine Mammals: Pacific Walrus Case Study
Journal of Environmental Management. Oct, 2009 | Pubmed ID: 19783356
Decision rules are the agreed-upon points at which specific management interventions are initiated. For marine mammal management under the U.S. Marine Mammal Protection Act (MMPA), decision rules are usually based on either a numeric population or biological-removal approach. However, for walrus and other ice-associated pinnipeds, the inability to reliably assess population numbers or biological removals highlights a significant gap in the MMPA, particularly when the Arctic environment is rapidly changing. We describe the MMPA's ecosystem-based management goals, and why managers have bypassed these goals in favor of an approach that depends upon numerical population assessment. We then revisit the statute's primary goals in light of current knowledge about the Pacific walrus ecosystem and new developments in environmental governance. We argue that to monitor and respond to changes in the walrus ecosystem, decision rules should be based on scientific criteria that depend less on the currently-impractical goal of accurately enumerating population size and trends, or removals from that population. Rather, managers should base decisions on ecological needs and observed ecological changes. To implement this approach would require an amendment to the MMPA that supports filling the gap in management with achievable decision rules. Alternatively, walrus and other ice-associated pinnipeds will remain largely unmanaged during a period of profound environmental change.
3D Collagen Orientation Study of the Human Cornea Using X-ray Diffraction and Femtosecond Laser Technology
Investigative Ophthalmology & Visual Science. Nov, 2009 | Pubmed ID: 19516010
To study the distribution and predominant orientations of fibrillar collagen at different depths throughout the entire thickness of the human cornea. This information will form the basis of a full three-dimensional reconstruction of the preferred orientations of corneal lamellae.
Techniques in Hand & Upper Extremity Surgery. Jun, 2009 | Pubmed ID: 19516140
Cochrane Database of Systematic Reviews (Online). 2009 | Pubmed ID: 19821362
Impaction grafting is a technique to restore bone loss both in the femur and the acetabulum during revision hip arthroplasty surgery. Initially impaction grafting was undertaken using fresh frozen femoral head allografts that were milled to create morselized bone pieces that could be impacted to create a neo-cancellous bone bed prior to cementation of the new implant. Results of medium and long term outcome studies have shown variable results using this technique. Currently both processed and non-processed allograft bone are used and the purpose of this review was to analyse the evidence for both.
FEBS Letters. Nov, 2009 | Pubmed ID: 19833129
The E3 ubiqutin ligase, murne double-minute clone 2 (MDM2), promotes the degradation of p53 under normal homeostatic conditions. Several serine residues within the acidic domain of MDM2 are phosphorylated to maintain its activity but become hypo-phosphorylated following DNA damage, leading to inactivation of MDM2 and induction of p53. However, the signalling pathways that mediate these phosphorylation events are not fully understood. Here we show that the oncogenic and cell cycle-regulatory protein kinase, polo-like kinase-1 (PLK1), phosphorylates MDM2 at one of these residues, Ser260, and stimulates MDM2-mediated turnover of p53. These data are consistent with the idea that deregulation of PLK1 during tumourigenesis may help suppress p53 function.
The Significance of Degenerate Processes to Enantioselective Olefin Metathesis Reactions Promoted by Stereogenic-at-Mo Complexes
Journal of the American Chemical Society. Nov, 2009 | Pubmed ID: 19842640
The present study provides spectroscopic and experimental evidence demonstrating that degenerate metathesis is critical to the effectiveness of this emerging class of chiral catalysts. Isolation and X-ray characterization of both diastereomeric complexes, as well as an examination of the reactivity and enantioselectivity patterns exhibited by such initiating neophylidenes in promoting ring-closing metathesis processes, are disclosed. Only when sufficient amounts of ethylene are generated and inversion at Mo through degenerate processes occurs at a sufficiently rapid rate is high enantioselectivity achieved, irrespective of the stereochemical identity of the initiating alkylidene (Curtin-Hammett kinetics). With diastereomeric metal complexes that undergo rapid interconversion, stereomutation at the metal center becomes inconsequential, and stereoselective synthesis of a chiral catalyst is not required.
Cell Cycle (Georgetown, Tex.). Dec, 2009 | Pubmed ID: 19887906
The Effects of Intraoperative Positioning on Patients Undergoing Early Definitive Care for Femoral Shaft Fractures
Journal of Orthopaedic Trauma. Oct, 2009 | Pubmed ID: 19897981
To determine if there is a difference in morbidity and mortality in orthopaedic trauma patients with femoral shaft fractures undergoing early definitive care with intramedullary (IM) nails in the supine versus the lateral position.
Current Eye Research. Jun, 2009 | Pubmed ID: 19899984
The purpose of this study is to compare the structural integrity of bovine lenses using small-angle X-ray diffraction techniques, before and after freezing, using both liquid nitrogen and a -20 degrees C freezer to understand the molecular changes that occur and to see if any permanent structural changes result from the freezing and thawing process.
The Use of X-ray Scattering Techniques to Quantify the Orientation and Distribution of Collagen in the Corneal Stroma
Progress in Retinal and Eye Research. Sep, 2009 | Pubmed ID: 19577657
The bulk of the corneal stroma is comprised of a layered network of fibrillar collagen. Determining the architecture of this unique structure may help us to better understand the cornea's biomechanical and optical function. The analysis of diffraction patterns obtained when X-rays are passed through the regularly arranged collagen molecules and fibrils of the stromal matrix yields quantitative data on fibrillar organisation, including the orientation and distribution of collagen lamellae within the corneal plane. In recent years, by exploiting the radiation from powerful synchrotron sources, techniques have been developed to enable the mapping of collagen fibril, and therefore lamellar, directions across whole corneas. This article aims to summarise the use of X-ray diffraction to map the orientation and distribution of collagen in the corneal stroma. The implications of the knowledge gained so far are discussed in relation to the optical and biomechanical properties of the cornea, and their alteration due to disease and surgical intervention.
In Vivo Bioluminescent Imaging of Schwann Cells in a Poly(DL-lactide-epsilon-caprolactone) Nerve Guide
Muscle & Nerve. Nov, 2009 | Pubmed ID: 19618440
Nerve guides seeded with Schwann cells (SCs) promote axonal regeneration in peripheral nerve lesions. We examined the applicability of bioluminescent imaging (BLI) for monitoring the fate of SCs in nerve guides after implantation. Rat SCs were transfected with the firefly luciferase (Fluc) gene and subsequently seeded in nerve guides, which were implanted subcutaneously in rats. In vivo bioluminescence of transfected SCs (Fluc-SCs) was assessed with a BLI system. Scans were validated ex vivo using immunocytochemistry and electron microscopy. We found that BLI enables longitudinal in vivo monitoring of Fluc-SCs, given that proper access of luciferin to the cells is assured.
Environmental Health Perspectives. Aug, 2009 | Pubmed ID: 19672401
The southern United States (excluding Florida) has the highest age-adjusted rate of cardiovascular disease (CVD) in the country, with African Americans having a higher prevalence of CVD than Caucasians. Paraoxonase-1 (PON1), an enzyme associated with high-density lipoprotein particles, participates both in the hydrolysis of oxidized lipids (thus protecting against atherosclerosis) and in the hydrolysis of organophosphates. Higher paraoxonase activity has been associated with lower risk of atherosclerosis.
Emergency Medicine Australasia : EMA. Aug, 2009 | Pubmed ID: 19682019
To survey Fellows of the Australasian College for Emergency Medicine (FACEM) on how a range of factors influenced their decision to accept their most recent position. To compare this information between rural and metropolitan FACEM.
Latency to Facial Expression Change Following Noxious Stimulation in Infants is Dependent on Postmenstrual Age
Pain. Nov, 2009 | Pubmed ID: 19682794
Change in facial expression over a fixed time after a noxious stimulus is the key measure used to calculate pain scores in preterm and newborn infants. We hypothesised that the latency of facial motor responses would be longer in the youngest premature infants and that behavioural scoring methods of pain may need to take this into account. One hundred and seventy-two clinically required heel lances were performed in 95 infants from 25 to 44 weeks postmenstrual age (PMA). Sixty-four percentage of the heel lances evoked a change in facial expression. Change in facial expression was observed in infants across the whole age range from 25 weeks PMA and the latency to the facial expression response ranged from 1 to 17s. Latency to facial expression change was dependent on the infants' PMA at the time of the heel lance. Infants below 32 weeks PMA had a significantly longer latency to change in facial expression than older infants (54% increase in infants below 32 weeks; p < 0.001). Sleep state and presence of brain damage (IVH grades 1-4) did not significantly increase the latency (p > 0.05 for each variable). Intravenous morphine at the time of the heel lance significantly increased the latency to facial expression response (p < 0.001) but the analysis shows that latency is highly dependent on PMA independent of morphine administration. These findings highlight developmental changes underlying infant behaviour that are critically important if pain scores are to be correctly interpreted.
Plexiform Malignant Peripheral Nerve Sheath Tumour of Infancy and Childhood of the Index Finger: Surgical Treatment
Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery / Nordisk Plastikkirurgisk Forening [and] Nordisk Klubb for Handkirurgi. 2009 | Pubmed ID: 19688647
We describe a rare case of plexiform malignant peripheral nerve sheath tumour (MPNST) of infancy and childhood in a 3.5-year-old girl. The tumour was located in the proximal phalanx of the left index finger. After initial excisions and a ray amputation, exarticulation of the third and fourth rays was required.
Ecological Applications : a Publication of the Ecological Society of America. Jul, 2009 | Pubmed ID: 19688919
A single ecosystem dominates the Midwestern United States, occupying 26 million hectares in five states alone: the corn-soybean agroecosystem [Zea mays L.-Glycine max (L.) Merr.]. Nitrogen (N) fertilization could influence the soil carbon (C) balance in this system because the corn phase is fertilized in 97-100% of farms, at an average rate of 135 kg N x ha(-1) x yr(-1). We evaluated the impacts on two major processes that determine the soil C balance, the rates of organic-carbon (OC) inputs and decay, at four levels of N fertilization, 0, 90, 180, and 270 kg/ha, in two long-term experimental sites in Mollisols in Iowa, USA. We compared the corn-soybean system with other experimental cropping systems fertilized with N in the corn phases only: continuous corn for grain; corn-corn-oats (Avena sativa L.)-alfalfa (Medicago sativa L.; corn-oats-alfalfa-alfalfa; and continuous soybean. In all systems, we estimated long-term OC inputs and decay rates over all phases of the rotations, based on long-term yield data, harvest indices (HI), and root:shoot data. For corn, we measured these two ratios in the four N treatments in a single year in each site; for other crops we used published ratios. Total OC inputs were calculated as aboveground plus belowground net primary production (NPP) minus harvested yield. For corn, measured total OC inputs increased with N fertilization (P < 0.05, both sites). Belowground NPP, comprising only 6-22% of total corn NPP, was not significantly influenced by N fertilization. When all phases of the crop rotations were evaluated over the long term, OC decay rates increased concomitantly with OC input rates in several systems. Increases in decay rates with N fertilization apparently offset gains in carbon inputs to the soil in such a way that soil C sequestration was virtually nil in 78% of the systems studied, despite up to 48 years of N additions. The quantity of belowground OC inputs was the best predictor of long-term soil C storage. This indicates that, in these systems, in comparison with increased N-fertilizer additions, selection of crops with high belowground NPP is a more effective management practice for increasing soil C sequestration.
Esophageal Pressure Topography Criteria Indicative of Incomplete Bolus Clearance: a Study Using High-resolution Impedance Manometry
The American Journal of Gastroenterology. Nov, 2009 | Pubmed ID: 19690527
This study used high-resolution impedance manometry (HRIM) to determine pressure topography thresholds of peristaltic integrity predictive of incomplete esophageal bolus clearance.
The Journal of Experimental Biology. Sep, 2009 | Pubmed ID: 19717672
Mice from four lines bred for high voluntary wheel activity run approximately 3-fold more revolutions per day and have elevated maximal oxygen consumption during forced treadmill exercise, as compared with four unselected control (C) lines. We hypothesized that these high runner (HR) lines would have greater treadmill endurance-running capacity. Ninety-six mice from generation 49 were familiarized with running on a motorized treadmill for 3 days. On days 4 and 5, mice were given an incremental speed test (starting at 20 m min(-1), increased 1.5 m min(-1) every 2 min) and endurance was measured as the total time or distance run to exhaustion. Blood samples were taken to measure glucose and lactate concentrations at rest during the photophase, during peak nightly wheel running, and immediately following the second endurance test. Individual differences in endurance time were highly repeatable between days (r=0.79), and mice tended to run longer on the second day (paired t-test, P<0.0001). Blood glucose following the treadmill test was low for all animals ( approximately 53 mg dl(-1)) and lactate was high ( approximately 6.5 mmol l(-1)), suggesting that exhaustion occurred. The HR lines had significantly higher endurance than the C lines (1-tailed P<0.05), whether or not body mass was used as a covariate in the analysis. The relationship between line means for wheel running and treadmill endurance differed between the sexes, reinforcing previous studies that indicate sex-specific responses to selective breeding. HR mice appear to have a higher endurance capacity than reported in the literature for inbred strains of mice or transgenics intended to enhance endurance.
The Journal of Biological Chemistry. Nov, 2009 | Pubmed ID: 19759023
The ubiquitin ligase murine double minute clone 2 (MDM2) mediates ubiquitination and degradation of the tumor suppressor p53. The activation and stabilization of p53 by contrast is maintained by enzymes catalyzing p53 phosphorylation and acetylation. Casein kinase 1 (CK1) is one such enzyme; it stimulates p53 after transforming growth factor-beta treatment, irradiation, or DNA virus infection. We analyzed whether CK1 regulates p53 protein stability in unstressed conditions. Depletion of CK1 using small interfering RNA or inhibition of CK1 using the kinase inhibitor (D4476) activated p53 and destabilized E2F-1, indicating that steady-state levels of these proteins are controlled by CK1. Co-immunoprecipitation of endogenous CK1 with MDM2 occurred in undamaged cells, indicating the existence of a stable multiprotein complex, and as such, we evaluated whether the MDM2 Nutlin had similar pharmacological properties to the CK1 inhibitor D4476. Indeed, D4476 or Nutlin treatments resulted in the same p53 and E2F-1 steady-state protein level changes, indicating that the MDM2 x CK1 complex is both a negative regulator of p53 and a positive regulator of E2F-1 in undamaged cells. Although the treatment of cells with D4476 resulted in a partial p53-dependent growth arrest, the induction of p53-independent apoptosis by D4476 suggested a critical role for the MDM2 x CK1 complex in maintaining E2F-1 anti-apoptotic signaling. These data highlighting a pharmacological similarity between MDM2 and CK1 small molecule inhibitors and the fact that CK1 and MDM2 form a stable complex suggest that the MDM2 x CK1 complex is a component of a genetic pathway that co-regulates the stability of the p53 and E2F-1 transcription factors.
Cold Spring Harbor Perspectives in Biology. Dec, 2009 | Pubmed ID: 20457558
The p53 protein is modified by as many as 50 individual posttranslational modifications. Many of these occur in response to genotoxic or nongenotoxic stresses and show interdependence, such that one or more modifications can nucleate subsequent events. This interdependent nature suggests a pathway that operates through multiple cooperative events as opposed to distinct functions for individual, isolated modifications. This concept, supported by recent investigations, which provide exquisite detail as to how various modifications mediate precise protein-protein interactions in a cooperative manner, may explain why knockin mice expressing p53 proteins substituted at one or just a few sites of modification typically show only subtle effects on p53 function. The present article focuses on recent, exciting progress and develops the idea that the impact of modification on p53 function is achieved through collective and integrated events.
Estimating Genome-wide IBD Sharing from SNP Data Via an Efficient Hidden Markov Model of LD with Application to Gene Mapping
Bioinformatics (Oxford, England). Jun, 2010 | Pubmed ID: 20529903
Association analysis is the method of choice for studying complex multifactorial diseases. The premise of this method is that affected persons contain some common genomic regions with similar SNP alleles and such areas will be found in this analysis. An important disadvantage of GWA studies is that it does not distinguish between genomic areas that are inherited from a common ancestor [identical by descent (IBD)] and areas that are identical merely by state [identical by state (IBS)]. Clearly, areas that can be marked with higher probability as IBD and have the same correlation with the disease status of identical areas that are more probably only IBS, are better candidates to be causative, and yet this distinction is not encoded in standard association analysis.
The Journal of Pediatrics. Nov, 2010 | Pubmed ID: 20580018
To estimate the rates of hospitalization with seasonal influenza in children aged <18 years from a large, diverse surveillance area during 2003 to 2008.
Influenza-associated Pneumonia in Children Hospitalized with Laboratory-confirmed Influenza, 2003-2008
The Pediatric Infectious Disease Journal. Jul, 2010 | Pubmed ID: 20589966
Pneumonia is one of the most common complications in children hospitalized with influenza. We describe hospitalized children with influenza-associated pneumonia and associated risk indicators.
Wood Smoke Exposure and Gene Promoter Methylation Are Associated with Increased Risk for COPD in Smokers
American Journal of Respiratory and Critical Care Medicine. Nov, 2010 | Pubmed ID: 20595226
Wood smoke-associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.
Klebsiella Pneumoniae-triggered DC Recruit Human NK Cells in a CCR5-dependent Manner Leading to Increased CCL19-responsiveness and Activation of NK Cells
European Journal of Immunology. Nov, 2010 | Pubmed ID: 20865789
Besides their role in destruction of altered self-cells, NK cells have been shown to potentiate T-cell responses by interacting with DC. To take advantage of NK-DC crosstalk in therapeutic DC-based vaccination for infectious diseases and cancer, it is essential to understand the biology of this crosstalk. We aimed to elucidate the in vitro mechanisms responsible for NK-cell recruitment and activation by DC during infection. To mimic bacterial infection, DC were exposed to a membrane fraction of Klebsiella pneumoniae, which triggers TLR2/4. DC matured with these bacterial fragments can actively recruit NK cells in a CCR5-dependent manner. An additional mechanism of DC-induced NK-cell recruitment is characterized by the induction of CCR7 expression on CD56(dim) CD16(+) NK cells after physical contact with membrane fraction of K. pneumoniae-matured DC, resulting in an enhanced migratory responsiveness to the lymph node-associated chemokine CCL19. Bacterial fragment-matured DC do not only mediate NK-cell migration but also meet the prerequisites needed for augmentation of NK-cell cytotoxicity and IFN-γ production, the latter of which contributes to Th1 polarization.
Exclusive Breastmilk Feeding in Maternity Care Facilities: the United States Breastfeeding Committee Toolkit
Breastfeeding Medicine : the Official Journal of the Academy of Breastfeeding Medicine. Oct, 2010 | Pubmed ID: 20942716
Progress in Neurobiology. Nov, 2010 | Pubmed ID: 20950667
Peripheral nerve injuries that induce gaps larger than 1-2 cm require bridging strategies for repair. Autologous nerve grafts are still the gold standard for such interventions, although alternative treatments, as well as treatments to improve the therapeutic efficacy of autologous nerve grafting are generating increasing interest. Investigations are still mostly experimental, although some clinical studies have been undertaken. In this review, we aim to describe the developments in bridging technology which aim to replace the autograft. A multi-disciplinary approach is of utmost importance to develop and optimise treatments of the most challenging peripheral nerve injuries.
Histopathology. Oct, 2010 | Pubmed ID: 20955385
Mucin 1 (MUC1) is an important tumour-associated antigen (TAA), both overexpressed and aberrantly glycosylated in adenocarcinomas. The aim of this study was to examine the MUC1-glycosylation status of primary ovarian adenocarcinomas and metastatic lesions.
Assessing the Purity of Metal-organic Frameworks Using Photoluminescence: MOF-5, ZnO Quantum Dots, and Framework Decomposition
Journal of the American Chemical Society. Nov, 2010 | Pubmed ID: 20961048
Photoluminescence (PL) spectroscopy was used to characterize nanoscale ZnO impurities, amine-donor charge-transfer exciplexes, and framework decomposition in samples of MOF-5 prepared by various methods. The combined results cast doubt on previous reports describing MOF-5 as a semiconductor and demonstrate that PL as a tool for characterizing MOF purity possesses advantages such as simplicity, speed, and sensitivity over currently employed powder XRD MOF characterization methods.
Cell Cycle (Georgetown, Tex.). Oct, 2010 | Pubmed ID: 20962589
PLK1 is a critical mediator of G₂/M cell cycle transition that is inactivated and depleted as part of the DNA damage-induced G₂/M checkpoint. Here we show that downregulation of PLK1 expression occurs through a transcriptional repression mechanism and that p53 is both necessary and sufficient to mediate this effect. Repression of PLK1 by p53 occurs independently of p21 and of arrest at G₁/S where PLK1 levels are normally repressed in a cell cycle-dependent manner through a CDE/CHR element. Chromatin immunoprecipitation analysis indicates that p53 is present on the PLK1 promoter at two distinct sites termed p53RE1 and p53RE2. Recruitment of p53 to p53RE2, but not to p53RE1, is stimulated in response to DNA damage and/or p53 activation and is coincident with repression-associated changes in the chromatin. Downregulation of PLK1 expression by p53 is relieved by the histone deacetylase inhibitor, trichostatin A, and involves recruitment of histone deacetylase to the vicinity of p53RE2, further supporting a transcriptional repression mechanism. Additionally, wild type, but not mutant, p53 represses expression of the PLK1 promoter when fused upstream of a reporter gene. Silencing of PLK1 expression by RNAi interferes with cell cycle progression consistent with a role in the p53-mediated checkpoint. These data establish PLK1 as a direct transcriptional target of p53, independently of p21, that is required for efficient G₂/M arrest.
Biochemistry. Aug, 2010 | Pubmed ID: 20597513
Steady-state kinetic analysis of focal adhesion kinase-1 (FAK1) was performed using radiometric measurement of phosphorylation of a synthetic peptide substrate (Ac-RRRRRRSETDDYAEIID-NH(2), FAK-tide) which corresponds to the sequence of an autophosphorylation site in FAK1. Initial velocity studies were consistent with a sequential kinetic mechanism, for which apparent kinetic values k(cat) (0.052 +/- 0.001 s(-1)), K(MgATP) (1.2 +/- 0.1 microM), K(iMgATP) (1.3 +/- 0.2 microM), K(FAK-tide) (5.6 +/- 0.4 microM), and K(iFAK-tide) (6.1 +/- 1.1 microM) were obtained. Product and dead-end inhibition data indicated that enzymatic phosphorylation of FAK-tide by FAK1 was best described by a random bi bi kinetic mechanism, for which both E-MgADP-FAK-tide and E-MgATP-P-FAK-tide dead-end complexes form. FAK1 catalyzed the betagamma-bridge:beta-nonbridge positional oxygen exchange of [gamma-(18)O(4)]ATP in the presence of 1 mM [gamma-(18)O(4)]ATP and 1.5 mM FAK-tide with a progressive time course which was commensurate with catalysis, resulting in a rate of exchange to catalysis of k(x)/k(cat) = 0.14 +/- 0.01. These results indicate that phosphoryl transfer is reversible and that a slow kinetic step follows formation of the E-MgADP-P-FAK-tide complex. Further kinetic studies performed in the presence of the microscopic viscosogen sucrose revealed that solvent viscosity had no effect on k(cat)/K(FAK-tide), while k(cat) and k(cat)/K(MgATP) were both decreased linearly at increasing solvent viscosity. Crystallographic characterization of inactive versus AMP-PNP-liganded structures of FAK1 showed that a large conformational motion of the activation loop upon ATP binding may be an essential step during catalysis and would explain the viscosity effect observed on k(cat)/K(m) for MgATP but not on k(cat)/K(m) for FAK-tide. From the positional isotope exchange, viscosity, and structural data it may be concluded that enzyme turnover (k(cat)) is rate-limited by both reversible phosphoryl group transfer (k(forward) approximately 0.2 s(-1) and k(reverse) approximately 0.04 s(-1)) and a slow step (k(conf) approximately 0.1 s(-1)) which is probably the opening of the activation loop after phosphoryl group transfer but preceding product release.
Current Eye Research. Jul, 2010 | Pubmed ID: 20597644
Collagen fibrils in the corneal stroma in macular corneal dystrophy, on average, are more closely spaced than in the normal cornea. This study was conducted to investigate if this occurs uniformly across the stroma or is more prevalent at certain stromal depths.
American Journal of Human Genetics. Jul, 2010 | Pubmed ID: 20598275
Primary microcephaly is a rare condition in which brain size is substantially diminished without other syndromic abnormalities. Seven autosomal loci have been genetically mapped, and the underlying causal genes have been identified for MCPH1, MCPH3, MCPH5, MCPH6, and MCPH7 but not for MCPH2 or MCPH4. The known genes play roles in mitosis and cell division. We ascertained three families from an Eastern Canadian subpopulation, each with one microcephalic child. Homozygosity analysis in two families using genome-wide dense SNP genotyping supported linkage to the published MCPH4 locus on chromosome 15q21.1. Sequencing of coding exons of candidate genes in the interval identified a nonconservative amino acid change in a highly conserved residue of the centrosomal protein CEP152. The affected children in these two families were both homozygous for this missense variant. The third affected child was compound heterozygous for the missense mutation plus a second, premature-termination mutation truncating a third of the protein and preventing its localization to centrosomes in transfected cells. CEP152 is the putative mammalian ortholog of Drosphila asterless, mutations in which affect mitosis in the fly. Published data from zebrafish are also consistent with a role of CEP152 in centrosome function. By RT-PCR, CEP152 is expressed in the embryonic mouse brain, similar to other MCPH genes. Like some other MCPH genes, CEP152 shows signatures of positive selection in the human lineage. CEP152 is a strong candidate for the causal gene underlying MCPH4 and may be an important gene in the evolution of human brain size.
Pediatrics. Aug, 2010 | Pubmed ID: 20603262
Multiple studies have revealed inadequacies in breastfeeding education during residency, and results of recent studies have confirmed that attitudes of practicing pediatricians toward breastfeeding are deteriorating. In this we study evaluated whether a residency curriculum improved physician knowledge, practice patterns, and confidence in providing breastfeeding care and whether implementation of this curriculum was associated with increased breastfeeding rates in patients.
The EMBO Journal. Sep, 2010 | Pubmed ID: 20657550
p53 mediates DNA damage-induced cell-cycle arrest, apoptosis, or senescence, and it is controlled by Mdm2, which mainly ubiquitinates p53 in the nucleus and promotes p53 nuclear export and degradation. By searching for the kinases responsible for Mdm2 S163 phosphorylation under genotoxic stress, we identified S6K1 as a multifaceted regulator of Mdm2. DNA damage activates mTOR-S6K1 through p38alpha MAPK. The activated S6K1 forms a tighter complex with Mdm2, inhibits Mdm2-mediated p53 ubiquitination, and promotes p53 induction, in addition to phosphorylating Mdm2 on S163. Deactivation of mTOR-S6K1 signalling leads to Mdm2 nuclear translocation, which is facilitated by S163 phosphorylation, a reduction in p53 induction, and an alteration in p53-dependent cell death. These findings thus establish mTOR-S6K1 as a novel regulator of p53 in DNA damage response and likely in tumorigenesis. S6K1-Mdm2 interaction presents a route for cells to incorporate the metabolic/energy cues into DNA damage response and links the aging-controlling Mdm2-p53 and mTOR-S6K pathways.
Adult Hospitalizations for Laboratory-positive Influenza During the 2005-2006 Through 2007-2008 Seasons in the United States
The Journal of Infectious Diseases. Sep, 2010 | Pubmed ID: 20677944
Rates of influenza-associated hospitalizations in the United States have been estimated using modeling techniques with data from pneumonia and influenza hospitalization discharge diagnoses, but they have not been directly estimated from laboratory-positive cases.
The Journal of Bone and Joint Surgery. British Volume. Sep, 2010 | Pubmed ID: 20798444
The management of the patella during total knee replacement is controversial. In some studies the absence of patellar resurfacing results in residual anterior knee pain in over 10% of patients. One form of treatment which may be used in an endeavour to reduce this is circumferential patellar rim electrocautery. This is believed to partially denervate the patella. However, there is no evidence of the efficacy of this procedure, nor do we know if it results in harm. A retrospective comparative cohort study was performed of 192 patients who had undergone a primary total knee replacement with the porous coated Low Contact Stress rotating platform prosthesis without patellar resurfacing between 2003 and 2007. In 98 patients circumferential electrocautery of the patellar rim was performed and in 94 patients it was not. The two groups were matched for gender and age. The general Oxford Knee Score and the more specific patellar score for anterior knee pain were used to assess patient outcomes a minimum of two years post-operatively. No statistically significant differences were noted between the groups for either scoring system (p = 0.41 and p = 0.87, respectively). Electrocautery of the patella rim did not improve the outcome scores after primary total knee replacement in our patients.
Oral Sucrose As an Analgesic Drug for Procedural Pain in Newborn Infants: a Randomised Controlled Trial
Lancet. Oct, 2010 | Pubmed ID: 20817247
Many infants admitted to hospital undergo repeated invasive procedures. Oral sucrose is frequently given to relieve procedural pain in neonates on the basis of its effect on behavioural and physiological pain scores. We assessed whether sucrose administration reduces pain-specific brain and spinal cord activity after an acute noxious procedure in newborn infants.
Cancer Research. Dec, 2010 | Pubmed ID: 21056992
The p53 tumor suppressor plays a major protective role in tumor prevention by coordinating changes in gene expression that lead to the elimination of cancer cells. Mage-A proteins comprise a family of metastasis-associated transcriptional regulators that potently inhibit p53 function. Here, we show that Mage-A interacts with 3 distinct peptides each of which is located within the DNA binding surface of the core domain of p53 and encompasses amino acids that are critical for site-specific DNA binding. These data suggest that Mage-A may block the association of p53 with its cognate sites in chromatin. Consistent with this idea, silencing of Mage-A expression leads to upregulation of several p53-responsive genes in a p53-dependent manner and stimulates by several fold the interaction of p53 with the p21, MDM2, and PUMA promoters. Notably, these effects can occur in the absence of genotoxic stress, leading in a p53-dependent manner, to cell-cycle delay and increased cell death. These data reveal a novel mechanism by which Mage-A proteins may suppress the p53 transcriptional program during tumor development and highlight the p53/Mage-A interaction as a prospective therapeutic target.
Ultrasound Guidance for Central Venous Catheter Placement in Australasian Emergency Departments: Potential Barriers to More Widespread Use
Emergency Medicine Australasia : EMA. Dec, 2010 | Pubmed ID: 21091873
To survey Fellows of the Australasian College for Emergency Medicine (FACEMs) in order to describe current ultrasound (US) usage during central venous catheter (CVC) placement and to compare practice and opinions between FACEMs routinely using US and those not.
Journal of Environmental Quality. Sep-Oct, 2010 | Pubmed ID: 21043276
Improved understanding of year-to-year late-spring soil nitrate test (LSNT) variability could help make it more attractive to producers. We test the ability of the Root Zone Water Quality Model (RZWQM) to simulate watershed-scale variability due to the LSNT, and we use the optimized model to simulate long-term field N dynamics under related conditions. Autoregressive techniques and the automatic parameter calibration program PEST were used to show that RZWQM simulates significantly lower nitrate concentration in discharge from LSNT treatments compared with areas receiving fall N fertilizer applications within the tile-drained Walnut Creek, Iowa, watershed (>5 mg NL(-1) difference for the third year of the treatment, 1999). This result is similar to field-measured data from a paired watershed experiment. A statistical model we developed using RZWQM simulations from 1970 to 2005 shows that early-season precipitation and early-season temperature account for 90% of the interannual variation in LSNT-based fertilizer N rates. Long-term simulations with similar average N application rates for corn (Zea mays L.) (151 kg N ha(-1)) show annual average N loss in tile flow of 20.4, 22.2, and 27.3 kg N ha(-1) for LSNT, single spring, and single fall N applications. These results suggest that (i) RZWQM is a promising tool to accurately estimate the water quality effects of LSNT; (ii) the majority of N loss difference between LSNT and fall applications is because more N remains in the root zone for crop uptake; and (iii) year-to-year LSNT-based N rate differences are mainly due to variation in early-season precipitation and temperature.
Is Homatropine 5% Effective in Reducing Pain Associated with Corneal Abrasion when Compared with Placebo? A Randomized Controlled Trial
Emergency Medicine Australasia : EMA. Dec, 2010 | Pubmed ID: 21143399
To compare the change in visual analogue scale (VAS) pain ratings over 24 h following mechanical corneal abrasion between patients receiving sixth hourly drops of either 5% homatropine or placebo.
PloS One. 2010 | Pubmed ID: 21151976
The rat is the preferred experimental animal in many biological studies. With the recent derivation of authentic rat embryonic stem (ES) cells it is now feasible to apply state-of-the art genetic engineering in this species using homologous recombination. To establish whether rat ES cells are amenable to in vivo recombination, we tested targeted disruption of the hypoxanthine phosphoribosyltransferase (hprt) locus in ES cells derived from both inbred and outbred strains of rats. Targeting vectors that replace exons 7 and 8 of the hprt gene with neomycinR/thymidine kinase selection cassettes were electroporated into male Fisher F344 and Sprague Dawley rat ES cells. Approximately 2% of the G418 resistant colonies also tolerated selection with 6-thioguanine, indicating inactivation of the hprt gene. PCR and Southern blot analysis confirmed correct site-specific targeting of the hprt locus in these clones. Embryoid body and monolayer differentiation of targeted cell lines established that they retained differentiation potential following targeting and selection. This report demonstrates that gene modification via homologous recombination in rat ES cells is efficient, and should facilitate implementation of targeted, genetic manipulation in the rat.
Journal of Toxicology and Environmental Health. Part B, Critical Reviews. Oct, 2010 | Pubmed ID: 21170809
There is a need to define exposure-response curves for both Cu excess and deficiency to assist in determining the acceptable range of oral intake. A comprehensive database has been developed where different health outcomes from elevated and deficient Cu intakes were assigned ordinal severity scores to create common measures of response. A generalized linear model for ordinal data was used to estimate the probability of response associated with dose, duration and severity. The model can account for differences in animal species, the exposure medium (drinking water and feed), age, sex, and solubility. Using this model, an optimal intake level of 2.6 mg Cu/d was determined. This value is higher than the current U.S. recommended dietary intake (RDI; 0.9 mg/d) that protects against toxicity from Cu deficiency. It is also lower than the current tolerable upper intake level (UL; 10 mg/d) that protects against toxicity from Cu excess. Compared to traditional risk assessment approaches, categorical regression can provide risk managers with more information, including a range of intake levels associated with different levels of severity and probability of response. To weigh the relative harms of deficiency and excess, it is important that the results be interpreted along with the available information on the nature of the responses that were assigned to each severity score.
Proceedings of the Institution of Mechanical Engineers. Part H, Journal of Engineering in Medicine. Dec, 2010 | Pubmed ID: 21287823
As the population ages, the number of operations performed on bone is expected to increase. Diseases such as arthritis, tumours, and trauma can lead to defects in the skeleton requiring an operation to replace or restore the lost bone. Surgeons can use autografts, allografts, and/or bone graft substitutes to restore areas of bone loss. Surgical implants are also used in addition or in isolation to replace the diseased bone. This review considers the application of available bone grafts in different clinical settings. It also discusses recently introduced bioactive biomaterials and highlights the clinical difficulties and technological deficiencies that exist in our current surgical practice.
Drug, Healthcare and Patient Safety. 2010 | Pubmed ID: 21701631
Low-dose aspirin is widely used in the primary and secondary prevention of cardiovascular events, but is associated with a range of upper gastrointestinal side effects. In this review, we summarize the rationale for low-dose aspirin therapy, quantify the risk for upper gastrointestinal side effects, identify the risk factors involved, and provide an overview of preventive strategies, thereby focusing on the rationale and clinical utility of combining proton-pump inhibitors with low-dose aspirin.
The Journal of Arthroplasty. Sep, 2010 | Pubmed ID: 19963333
To determine whether alendronate alters the pseudomembrane inflammatory cytokine profile in patients with established aseptic osteolysis. A prospective, double-blind, randomized, controlled trial was conducted. Ten individuals listed for revision surgery for aseptic failure of a primary cemented arthroplasty were randomly assigned placebo/alendronate 70 mg once weekly for 8 weeks before revision surgery. Formalin-preserved pseudomembrane samples were paraffin-sectioned for immunohistochemical analysis to assess inflammatory cytokine protein expression. Polymerase chain reaction was carried out to assess expression of relevant mRNA. No significant difference was detected in the inflammatory cytokine protein or mRNA expression between groups. Alendronate 70 mg administered for an 8-week period before surgery did not alter the pseudomembrane inflammatory cytokine profile in patients with established aseptic osteolysis. Any potential biological effects may occur due to downstream effects on osteoclast and osteoblast function.
Catalytic Enantioselective Olefin Metathesis in Natural Product Synthesis. Chiral Metal-based Complexes That Deliver High Enantioselectivity and More
Angewandte Chemie (International Ed. in English). 2010 | Pubmed ID: 19967680
Chiral olefin metathesis catalysts enable chemists to access enantiomerically enriched small molecules with high efficiency; synthesis schemes involving such complexes can be substantially more concise than those that would involve enantiomerically pure substrates and achiral Mo alkylidenes or Ru-based carbenes. The scope of research towards design and development of chiral catalysts is not limited to discovery of complexes that are merely the chiral versions of the related achiral variants. A chiral olefin metathesis catalyst, in addition to furnishing products of high enantiomeric purity, can offer levels of efficiency, product selectivity and/or olefin stereoselectivity that are unavailable through the achiral variants. Such positive attributes of chiral catalysts (whether utilized in racemic or enantiomerically enriched form) should be considered as general, applicable to other classes of transformations.
Investigation of GammaE-crystallin Target Protein Binding to Bovine Lens Alpha-crystallin by Small-angle Neutron Scattering
Biochimica Et Biophysica Acta. Mar, 2010 | Pubmed ID: 20004233
alpha-Crystallin, one of the main constituent proteins in the crystalline lens, is an important molecular chaperone both within and outside the lens. Presently, the structural relationship between alpha-crystallin and its target proteins during chaperone action is poorly understood. It has been hypothesised that target proteins bind within a central cavity. Small-angle neutron-scattering (SANS) experiments in conjunction with isotopic substitution were undertaken to investigate the interaction of a target lens protein (gammaE-crystallin) with alpha-crystallin (alpha(H)) and to measure the radius of gyration (Rg) of the proteins and their binary complexes in solution under thermal stress. The size of the alpha(H) in D(2)O incubated at 65 degrees C increased from 69+/-3 to 81+/-5 A over 40 min, in good agreement with previously published small-angle X-ray scattering (SAXS) and SANS measurements. Deuterated gammaE-crystallin in H(2)O buffer (gammaE(D)/H(2)O) and hydrogenous gammaE-crystallin in D(2)O buffer (gammaE(H)/D(2)O) free in solution were of insufficient size and/or too dilute to provide any measurable scattering over the angular range used, which was selected primarily to investigate gammaE:alpha(H) complexes. The evolution of the aggregation size/shape as an indicator of alpha(H) chaperone action was monitored by recording the neutron scattering in different H:D solvent contrasts under thermally stressed conditions (65 degrees C) for binary mixtures of alpha(H), gammaE(H), and gammaE(D). It was found that Rg(alpha(H):gammaE(D)/D(2)O)>Rg(alpha(H):gammaE(H)/D(2)O)>Rg(alpha(H)/D(2)O) and that Rg(alpha(H):gammaE(H)/D(2)O) approximately Rg(alpha(H)/D(2)O). The relative sizes observed for the complexes weighted by the respective scattering powers of the various components imply that gammaE-crystallin binds in a central cavity of the alpha-crystallin oligomer, during chaperone action.
Collagen and Mature Elastic Fibre Organisation As a Function of Depth in the Human Cornea and Limbus
Journal of Structural Biology. Mar, 2010 | Pubmed ID: 19914381
A network of circumferentially oriented collagen fibrils exists in the periphery of the human cornea, and is thought to be pivotal in maintaining corneal biomechanical stability and curvature. However, it is unknown whether or not this key structural arrangement predominates throughout the entire corneal thickness or exists as a discrete feature at a particular tissue depth; or if it incorporates any elastic fibres and how, with respect to tissue depth, the circumcorneal annulus integrates with the orthogonally arranged collagen of the central cornea. To address these issues we performed a three-dimensional investigation of fibrous collagen and elastin architecture in the peripheral and central human cornea using synchrotron X-ray scattering and non-linear microscopy. This showed that the network of collagen fibrils circumscribing the human cornea is located in the posterior one-third of the tissue and is interlaced with significant numbers of mature elastic fibres which mirror the alignment of the collagen. The orthogonal arrangement of collagen in the central cornea is also mainly restricted to the posterior stromal layers. This information will aid the development of corneal biomechanical models aimed at explaining how normal corneal curvature is sustained and further predicting the outcome of surgical procedures.
Phosphorylation of Serine 392 in P53 is a Common and Integral Event During P53 Induction by Diverse Stimuli
Cellular Signalling. Mar, 2010 | Pubmed ID: 19932175
Post-translational modifications play important roles during the stabilisation and activation of p53 by various genotoxic and non-genotoxic stresses. Ser392 has been reported to be a major UV-stimulated phosphorylation site that is modified through the p38 MAPK pathway in a manner that may involve recruitment of CK2. Here we show that phosphorylation of Ser392 is an integral event that occurs not only in response to UV, but also during the induction of p53 by a range of stimuli including treatment of cells with the MDM2 inhibitor, Nutlin 3a. Strikingly, phosphorylation of Ser392 and Ser33 was also observed following induction of the p53 pathway by ARF which has previously been thought to induce p53 in a phosphorylation-independent manner. The induction of Ser392 phosphorylation by diverse stimuli can be explained by a common mechanism in which its phosphorylation at a low rate, coupled with the rapid turnover of p53, limits the accumulation of phosphorylated molecules until a stimulus stabilises p53 and allows the Ser392-phosphorylated p53 to accumulate. We also provide biological evidence that Ser392 phosphorylation is not mediated by a UV-associated route involving p38 MAPK, either directly or indirectly via CK2. These data suggest that, physiologically, Ser392 may be phosphorylated by an, as yet, unidentified protein kinase.
DNA Repair. Jan, 2010 | Pubmed ID: 19959401
Bacterial AlkB and three human AlkB homologues (ABH1, ABH2, and ABH3) are Fe(2+)/2-oxoglutarate-dependent oxygenases that directly repair alkylation-damaged DNA. Here, we show that ABH1 unexpectedly has a second activity, cleaving DNA at abasic (AP) sites such as those arising spontaneously from alkylation-dependent depurination reactions. The DNA cleavage activity of ABH1 does not require added Fe(2+) or 2-oxoglutarate, is not inhibited by EDTA, and is unaffected by mutation of the putative metal-binding residues, indicating that this activity arises from an active site distinct from that used for demethylation. AP-specific DNA cleavage was shown to occur by a lyase mechanism, rather than by hydrolysis, with the enzyme remaining associated with the DNA product. ABH1 can cleave at closely spaced AP-sites on opposite DNA strands yielding double-strand breaks in vitro and this reaction may relate to the physiological role of this unexpected AP lyase activity.
The Regulation of MDM2 by Multisite Phosphorylation--opportunities for Molecular-based Intervention to Target Tumours?
Seminars in Cancer Biology. Feb, 2010 | Pubmed ID: 19897041
The p53 tumour suppressor is a tightly controlled transcription factor that coordinates a broad programme of gene expression in response to various cellular stresses leading to the outcomes of growth arrest, senescence, or apoptosis. MDM2 is an E3 ubiquitin ligase that plays a key role in maintaining p53 at critical physiological levels by targeting it for proteasome-mediated degradation. Expression of the MDM2 gene is p53-dependent and thus p53 and MDM2 operate within a negative feedback loop in which p53 controls the levels of its own regulator. Induction and activation of p53 involves mainly the uncoupling of p53 from its negative regulators, principally MDM2 and MDMX, an MDM2-related and -interacting protein that inhibits p53 transactivation function. MDM2 is tightly regulated through various mechanisms including gene expression, protein turnover (mediated by auto-ubiquitylation), protein-protein interaction with key regulators, and post-translational modification, mainly, but not exclusively, by multisite phosphorylation. The purpose of the present article is to review our current knowledge of the signalling mechanisms that focus on MDM2, and indeed MDMX, through both phosphorylation mechanisms and peptide-docking events and to consider the wider implications of these regulatory events in the context of coordinated regulation of the p53 response. This analysis also provides an opportunity to consider the signalling pathways regulating MDM2 as potential targets for non-genotoxic therapies aimed at restoring p53 function in tumour cells.
Injury. Feb, 2010 | Pubmed ID: 19879577
Intramedullary nailing is the standard fixation method for displaced diaphyseal fractures of the tibia in adults. The bends in modern tibial nails allow for an easier insertion, enhance the 'bone-nail construct' stability, and reduce axial malalignments of the main fragments. Anecdotal clinical evidence indicates that current nail designs do not fit optimally for patients of Asian origin. The aim of this study was to develop a method to quantitatively assess the anatomical fitting of two different nail designs for Asian tibiae by utilising 3D computer modelling. We used 3D models of two different tibial nail designs (ETN (Expert Tibia Nail) and ETN-Proximal-Bend, Synthes), and 20 CT-based 3D cortex models of Japanese cadaver tibiae. With the aid of computer graphical methods, the 3D nail models were positioned inside the medullary cavity of the intact 3D tibia models. The anatomical fitting between nail and bone was assessed by the extent of the nail protrusion from the medullary cavity into the cortical bone, in a real bone this might lead to axial malalignments of the main fragments. The fitting was quantified in terms of the total surface area, and the maximum distance by which the nail was protruding into the cortex of the virtual bone model. In all 20 bone models, the total area of the nail protruding from the medullary cavity was smaller for the ETN-Proximal-Bend (average 540 mm(2)) compared to the ETN (average 1044 mm(2)). Also, the maximum distance of the nail protruding from the medullary cavity was smaller for the ETN-Proximal-Bend (average 1.2mm) compared to the ETN (average 2.7 mm). The differences were statistically significant (p<0.05) for both the total surface area and the maximum distance measurements. By utilising computer graphical methods it was possible to conduct a quantitative fit assessment of different nail designs. The ETN-Proximal-Bend shows a statistical significantly better intramedullary fit with less cortical protrusion than the original ETN. In addition to the application in implant design, the developed method could potentially be suitable for pre-operative planning enabling the surgeon to choose the most appropriate nail design for a particular patient.
In Vitro-differentiated T/natural Killer-cell Progenitors Derived from Human CD34+ Cells Mature in the Thymus
Blood. Jan, 2010 | Pubmed ID: 19828700
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a treatment option for patients with hematopoietic malignancies that is hampered by treatment-related morbidity and mortality, in part the result of opportunistic infections, a direct consequence of delayed T-cell recovery. Thymic output can be improved by facilitation of thymic immigration, known to require precommitment of CD34(+) cells. We demonstrate that Delta-like ligand-mediated predifferentiation of mobilized CD34(+) cells in vitro results in a population of thymocyte-like cells arrested at a T/natural killer (NK)-cell progenitor stage. On intrahepatic transfer to Rag2(-/-)gamma(c)(-/-) mice, these cells selectively home to the thymus and differentiate toward surface T-cell receptor-alphabeta(+) mature T cells considerably faster than animals transplanted with noncultured CD34(+) cells. This finding creates the opportunity to develop an early T-cell reconstitution therapy to combine with HSCT.
Journal of Thrombosis and Thrombolysis. May, 2010 | Pubmed ID: 19543695
To investigate the effect of aspirin on the platelets of survivors of myocardial infarction we correlated plasma salicylate level with platelet reactivity in ten patients and ten normal controls. The patients and controls were tested at the end of 2 week periods on 75, 150 and 300 mg aspirin daily by mouth. Platelet reactivity was measured, under high shear stress conditions, using cartridges containing adrenaline and adenosine diphosphate in a PFA-100 platelet function analyser. The time taken by the developing platelet aggregate to close an aperture in the collagen membrane of the cartridge, the closure time, was taken as an index of platelet reactivity. There was no difference in baseline haematocrit, platelet count or plasma vWF antigen level between the groups. There was a dose-dependent increase in closure time of the adrenaline containing cartridge in the controls (P < 0.001), but not in the patients (P = 0.08), compatible with a reduced anti-platelet effect of aspirin in the patients. Furthermore, plasma salicylate level was higher in the patient group (P < 0.05).
Differential Relative Sulfation of Keratan Sulfate Glycosaminoglycan in the Chick Cornea During Embryonic Development
Investigative Ophthalmology & Visual Science. Mar, 2010 | Pubmed ID: 19815728
To investigate structural remodeling of the developing corneal stroma concomitant with changing sulfation patterns of keratan sulfate (KS) glycosaminoglycan (GAG) epitopes during embryogenesis and the onset of corneal transparency.
The Relationship Between the Insulin-like Growth Factor-1 Axis, Weight Loss, an Inflammation-based Score and Survival in Patients with Inoperable Non-small Cell Lung Cancer
Clinical Nutrition (Edinburgh, Scotland). Apr, 2010 | Pubmed ID: 19748165
The involvement of a systemic inflammatory response, as evidenced by the Glasgow Prognostic Score (GPS), is associated with weight loss and poor outcome in patients with non-small cell lung cancer. There is good evidence that nutritional and functional decline in patients with advanced malignant disease is associated with catabolic changes in metabolism. However, defects in anabolism may also contribute towards nutritional decline in patients with cancer. The aim of the present study was to examine the relationship between IGF-1 and IGFBP-3, performance status, mGPS and survival in patients with inoperable NSCLC.
European Journal of Pain (London, England). Mar, 2010 | Pubmed ID: 19481484
While human infants can display distinctive behavioural and physiological spinal cord and brainstem responses to noxious stimulation, it is not known whether cortical neurons are specifically activated by noxious stimuli in newborns. Here, using a novel approach to time-lock an EEG recording to a clinically required heel lance, we show the presence of a distinct nociceptive-specific potential in newborn infants (35-39 weeks postmenstrual age). The potential can be observed in single trials in the central electrodes (Cz and CPz) and using principal component analysis is characterised by a positivity that occurs at approximately 560 ms post-stimulus (N420-P560; P, positive; N, negative). The magnitude of the nociceptive-specific potential is not dependent on sleep state, whereas an earlier potential (N150-P260-N430), which is sleep-state dependent, is evoked by both noxious and non-noxious stimulation. These results provide the first direct evidence of specific noxious-evoked neural activity in the infant brain and suggest that newborn infants are capable of the sensory-discriminative aspects of pain experience.
Microsurgery. 2010 | Pubmed ID: 20073033
This report describes two incidental findings of aberrant branches of the radial digital nerves in the middle finger of a 52-year-old man who cut himself with a grinding machine, and in the index finger of a 45-year-old female who sustained a flexor sheath infection following a dog bite. In both patients, two equally sized radial digital nerves were found and both nerves originated from one common digital nerve.
Journal of Toxicology and Environmental Health. Part A. 2010 | Pubmed ID: 20077279
Journal of Toxicology and Environmental Health. Part A. 2010 | Pubmed ID: 20077295
This article addresses the content of the workshop, including a panel discussion relevant to delineation of a path forward in relation to risk assessment of essential metals. The state of the art of risk assessment and associated issues for essential metals are outlined initially, followed by brief illustration by the case studies considered at the workshop (i.e., copper, zinc, and manganese). Approaches for the future testing strategies of essential metals are discussed in terms of options to increase efficiency and accuracy of assessments. Subsequently, recommendations for pragmatic next steps to advance progress and facilitate uptake by the regulatory risk assessment community are presented.
Investigative Ophthalmology & Visual Science. Jun, 2010 | Pubmed ID: 20089872
To characterize changes in corneal collagen arrangement during mouse postnatal development.
Influenza Testing and Antiviral Prescribing Practices Among Emergency Department Clinicians in 9 States During the 2006 to 2007 Influenza Season
Annals of Emergency Medicine. Jan, 2010 | Pubmed ID: 20116012
Influenza causes significant widespread illness each year. Emergency department (ED) clinicians are often first-line providers to evaluate and make treatment decisions for patients presenting with influenza. We sought to better understand ED clinician testing and treatment practices in the Emerging Infections Program Network, a federal, state, and academic collaboration that conducts active surveillance for influenza-associated hospitalizations.
Proposed Mode of Action of Benzene-induced Leukemia: Interpreting Available Data and Identifying Critical Data Gaps for Risk Assessment
Chemico-biological Interactions. Mar, 2010 | Pubmed ID: 20153303
Mode of action is defined as a series of key biological events leading to an observed toxicological effect (for example, metabolism to a toxic entity, cell death, regenerative repair and tumors). It contrasts with mechanism of action, which generally involves a detailed understanding of the molecular basis for an effect. A framework to consider the weight of evidence for hypothesized modes of action in animals and their relevance to humans, has been widely adopted and used by government agencies and international organizations. The framework, developed and refined through its application in case studies for principally non-DNA-reactive carcinogens, has more recently been extended to DNA-reactive carcinogens, non-cancer endpoints and different life stages. In addition to increasing transparency, use of the framework promotes consistency in decision-making concerning adequacy of weight of evidence, facilitates peer input and review and identifies critical research needs. The framework provides an effective tool to facilitate discussion between the research and risk assessment communities on critical data gaps, which if filled, would permit more refined estimates of risk. As a basis for additionally coordinating and focusing research on critical data gaps in a risk assessment context, five key events in the mode of action for benzene-induced leukemia are proposed: (1) benzene metabolism via Cytochrome P450, (2) the interaction of benzene metabolites with target cells in the bone marrow, (3) formation of initiated, mutated target cells, (4) selective proliferation of the mutated cells and (5) production of leukemia. These key events are considered in a framework analysis of human relevance as a basis to consider appropriate next steps in developing research strategies.
International Journal of Obesity (2005). Jun, 2010 | Pubmed ID: 20157317
Mice from a long-term selective breeding experiment for high voluntary wheel running offer a unique model to examine the contributions of genetic and environmental factors in determining the aspects of behavior and metabolism relevant to body-weight regulation and obesity. Starting with generation 16 and continuing through to generation 52, mice from the four replicate high runner (HR) lines have run 2.5-3-fold more revolutions per day as compared with four non-selected control (C) lines, but the nature of this apparent selection limit is not understood. We hypothesized that it might involve the availability of dietary lipids.
Structural Interactions Between Collagen and Proteoglycans Are Elucidated by Three-dimensional Electron Tomography of Bovine Cornea
Structure (London, England : 1993). Feb, 2010 | Pubmed ID: 20159468
Interactions between collagens and proteoglycans help define the structure and function of extracellular matrices. The cornea, which contains proteoglycans with keratan sulphate or chondroitin/dermatan sulphate glycosaminoglycan chains, is an excellent model system in which to study collagen-proteoglycan structures and interactions. Here, we present the first three-dimensional electron microscopic reconstructions of the cornea, and these include corneas from which glycosaminoglycans have been selectively removed by enzymatic digestion. Our reconstructions show that narrow collagen fibrils associate with sulphated proteoglycans that appear as extended, variable-length linear structures. The proteoglycan network appears to tether two or more collagen fibrils, and thus organize the matrix with enough spatial specificity to fulfill the requirements for corneal transparency. Based on the data, we propose that the characteristic pseudohexagonal fibril arrangement in cornea is controlled by the balance of a repulsive force arising from osmotic pressure and an attractive force due to the thermal motion of the proteoglycans.
Efflux-pump-derived Multiple Drug Resistance to Ethambutol Monotherapy in Mycobacterium Tuberculosis and the Pharmacokinetics and Pharmacodynamics of Ethambutol
The Journal of Infectious Diseases. Apr, 2010 | Pubmed ID: 20210628
Ethambutol is used for the treatment of tuberculosis in cases where there is isoniazid resistance. We examined the emergence of drug resistance to ethambutol monotherapy in pharmacokinetic-pharmacodynamic studies of a hollow-fiber system.
Ethambutol Optimal Clinical Dose and Susceptibility Breakpoint Identification by Use of a Novel Pharmacokinetic-pharmacodynamic Model of Disseminated Intracellular Mycobacterium Avium
Antimicrobial Agents and Chemotherapy. May, 2010 | Pubmed ID: 20231389
Ethambutol, together with a macrolide, is the backbone for treatment of disseminated Mycobacterium avium disease. However, at the standard dose of 15 mg/kg of body weight/day, ethambutol efficacy is limited. In addition, susceptibility breakpoints have consistently failed to predict clinical outcome. We performed dose-effect studies with extracellular M. avium as well as with bacilli within human macrophages. The maximal kill rate (E(max)) for ethambutol against extracellular bacilli was 5.54 log(10) CFU/ml, compared to 0.67 log(10) CFU/ml for intracellular M. avium, after 7 days of exposure. Thus, extracellular assays demonstrated high efficacy. We created a hollow-fiber system model of intracellular M. avium and performed microbial pharmacokinetic-pharmacodynamic studies using pharmacokinetics similar to those of ethambutol for humans. The E(max) in the systems was 0.79 log(10) CFU/ml with 7 days of daily therapy, so the kill rates approximated those encountered in patients treated with ethambutol monotherapy. Ratio of peak concentration to MIC (C(max)/MIC) was linked to microbial kill rate. The C(max)/MIC ratio needed to achieve the 90% effective concentration (EC(90)) in serum was 1.23, with a calculated intramacrophage C(max)/MIC ratio of 13. In 10,000 patient Monte Carlo simulations, doses of 15, 50, and 75 mg/kg achieved the EC(90) in 35.50%, 76.81%, and 86.12% of patients, respectively. Therefore, ethambutol doses of >or=50 mg/kg twice a week would be predicted to be better than current doses of 15 mg/kg for treatment of disseminated M. avium disease. New susceptibility breakpoints and critical concentrations of 1 to 2 mg/liter were identified for the determination of ethambutol-resistant M. avium in Middlebrook broth. Given that the modal MIC of clinical isolates is around 2 mg/liter, most isolates should be considered ethambutol resistant.
Gastroenterology. Jul, 2010 | Pubmed ID: 20303352
The therapeutic mechanisms of ribavirin for hepatitis C are unclear. Microarray analyses have shown that ribavirin increases induction of interferon-stimulated genes. We evaluated viral kinetics, serum cytokine expression, and viral mutagenesis during early stages of peginterferon therapy with and without ribavirin.
Anaesthesia. Apr, 2010 | Pubmed ID: 20377552
Regional anaesthesia can marvellously dull the pain (and limit some other complications) of trauma, surgery and childbirth. But like all powerful techniques, it may have complications. Here the complications of regional anaesthesia are reviewed. The risks, presentation and the management of these complications are discussed in turn.
Increased Tumor-specific CD8+ T Cell Induction by Dendritic Cells Matured with a Clinical Grade TLR-agonist in Combination with IFN-gamma
International Journal of Immunopathology and Pharmacology. Jan-Mar, 2010 | Pubmed ID: 20377993
The limited response rate of cancer patients treated with dendritic cell (DC)-based vaccines indicates that vast improvements remain necessary. In many murine tumour models it has been demonstrated that the use of innate triggers (e.g. TLR triggers) in the maturation of DC results in higher efficacy. However, as few of these innate triggers are generated clinical grade, there remains a great necessity to fill the gap between fundamental mouse studies and a clinical trial in humans. In the present study we used a TLR2/4-agonist (FMKp which is available clinical grade) in combination with IFN-gamma (FIcocktail) in the maturation of elutriated monocyte-derived DC and compared it with the most used DC in current clinical trials (TNF-alpha/PGE-2, i.e. TP-cocktail). In addition to the assessment of CD4+ T cell polarizing capacity, we compared the quantity and intrinsic quality of induced CD8+ T cells of 2 different DC maturation protocols with all cells from the same donor. Besides differences in the cytokine profile, which could be coupled to increased Th1 and Th17 polarization, we demonstrate in this study that FMKp/IFN-gamma matured DC are twice as effective in inducing cytotoxic T cells against known tumor antigens. Both DCs induced phenotypically equivalent effector memory CD8+ T cells that did not show a significant difference in their intrinsic capacity to kill tumor cells. These findings point to the therapeutic applicability of FI-DC as superior inducers of functional antigen-specific T cells. Their increased chemokine secretion is suggestive of a mechanism by which these DC may compensate for the limited migration observed for all ex vivo cultured DC when applied in patients.
Moxifloxacin Pharmacokinetics/pharmacodynamics and Optimal Dose and Susceptibility Breakpoint Identification for Treatment of Disseminated Mycobacterium Avium Infection
Antimicrobial Agents and Chemotherapy. Jun, 2010 | Pubmed ID: 20385862
Organisms of the Mycobacterium avium-intracellulare complex (MAC) have been demonstrated to be susceptible to moxifloxacin. However, clinical data on how to utilize moxifloxacin to treat disseminated MAC are scanty. In addition, there have been no moxifloxacin pharmacokinetic-pharmacodynamic (PK/PD) studies performed for MAC infection. We utilized an in vitro PK/PD model of intracellular MAC to study moxifloxacin PK/PD for disseminated disease. Moxifloxacin doses, based on a serum half-life of 12 h, were administered, and the 0- to 24-h area under the concentration-time curve (AUC(0-24)) to MIC ratios associated with 1.0 log(10) CFU/ml per week kill and 90% of maximal kill (EC(90)) were identified. The AUC(0-24)/MIC ratio associated with 1.0 log(10) CFU/ml kill was 17.12, and that with EC(90) was 391.56 (r(2) = 0.97). Next, the moxifloxacin MIC distribution in 102 clinical isolates of MAC was identified. The median MIC was 1 to 2 mg/liter. Monte Carlo simulations of 10,000 patients with disseminated MAC were performed to determine the probability that daily moxifloxacin doses of 400 and 800 mg/day would achieve or exceed 1.0 log(10) CFU/ml per week kill or EC(90). Doses of 400 and 800 mg/day achieved the AUC(0-24)/MIC ratio of 17.12 in 64% and 92% of patients, respectively. The critical concentration of moxifloxacin against MAC was identified as 0.25 mg/liter in Middlebrook media. The proposed susceptibility breakpoint means that a larger proportion of clinical isolates is resistant to moxifloxacin prior to therapy. For patients infected with susceptible isolates, however, 800 mg a day should be examined for safety and efficacy for disseminated M. avium disease.
Journal of the Royal Society, Interface / the Royal Society. Oct, 2010 | Pubmed ID: 20392712
An experimental study has been conducted to determine the stress-strain behaviour of human corneal tissue and how the behaviour varies with age. Fifty-seven well-preserved ex vivo donor corneas aged between 30 and 99 years were subjected to cycles of posterior pressure up to 60 mm Hg while monitoring their behaviour. The corneas were mechanically clamped along their ring of scleral tissue and kept in physiological conditions of temperature and hydration. The tissue demonstrated hyper-elastic pressure-deformation and stress-strain behaviour that closely matched an exponential trend. Clear stiffening (increased resistance to deformation) with age was observed in all loading cycles, and the rate of stiffness growth was nonlinear with bias towards older specimens. With a strong statistical association between stiffness and age (p < 0.05), it was possible to develop generic stress-strain equations that were suitable for all ages between 30 and 99 years. These equations, which closely matched the experimental results, depicted corneal stiffening with age in a form suitable for implementation in numerical simulations of ocular biomechanical behaviour.
Premature Infants Display Increased Noxious-evoked Neuronal Activity in the Brain Compared to Healthy Age-matched Term-born Infants
NeuroImage. Aug, 2010 | Pubmed ID: 20438855
This study demonstrates that infants who are born prematurely and who have experienced at least 40days of intensive or special care have increased brain neuronal responses to noxious stimuli compared to healthy newborns at the same postmenstrual age. We have measured evoked potentials generated by noxious clinically-essential heel lances in infants born at term (8 infants; born 37-40weeks) and in infants born prematurely (7 infants; born 24-32weeks) who had reached the same postmenstrual age (mean age at time of heel lance 39.2+/-1.2weeks). These noxious-evoked potentials are clearly distinguishable from shorter latency potentials evoked by non-noxious tactile sensory stimulation. While the shorter latency touch potentials are not dependent on the age of the infant at birth, the noxious-evoked potentials are significantly larger in prematurely-born infants. This enhancement is not associated with specific brain lesions but reflects a functional change in pain processing in the brain that is likely to underlie previously reported changes in pain sensitivity in older ex-preterm children. Our ability to quantify and measure experience-dependent changes in infant cortical pain processing will allow us to develop a more rational approach to pain management in neonatal intensive care.
Eye (London, England). Apr, 2010 | Pubmed ID: 19575034
Penetrating keratoplasty was performed on the right eye of a 51-year-old patient diagnosed with advanced bilateral keratoconus. Thirteen years later, an 8.5 mm regraft was required as a result of gross vascularisation, a poor epithelium, and suspected recurrent keratoconus. To learn more about the structural basis for graft failure, we examined the removed tissue for the presence of abnormalities in the stroma and limiting membranes.
The British Journal of Ophthalmology. Aug, 2010 | Pubmed ID: 19304581
Scant consideration has been given to the variation in structure of the human amniotic membrane (AM) at source or to the significance such differences might have on its clinical transparency. Therefore, we applied our experience of quantifying corneal transparency to AM.
Computer Methods in Biomechanics and Biomedical Engineering. Apr, 2011 | Pubmed ID: 20455154
An iterative method for the fit optimisation of a pre-contoured fracture fixation plate for a given bone data set is presented. Both plate shape optimisation and plate fit quantification are conducted in a virtual environment utilising computer graphical methods and 3D bone and plate models. Two optimised shapes of the undersurface of an existing distal medial tibia plate were generated based on a dataset of 45 3D bone models reconstructed from computed tomography image data of Japanese tibiae. The existing plate shape achieved an anatomical fit on 13% of tibiae from the dataset. Modified plate 1 achieved an anatomical fit for 42% and modified plate 2 a fit for 67% of the bones. If either modified plate 1 or plate 2 is used, then the anatomical fit can be increased to 82% for the same dataset. Issues pertaining to any further improvement in plate fit/shape are discussed.
Lower Rates of Dislocation with Increased Femoral Head Size After Primary Total Hip Replacement: a Five-year Analysis of NHS Patients in England
The Journal of Bone and Joint Surgery. British Volume. Jul, 2011 | Pubmed ID: 21705556
Increased femoral head size may reduce dislocation rates following total hip replacement. The National Joint Registry for England and Wales has highlighted a statistically significant increase in the use of femoral heads ≥ 36 mm in diameter from 5% in 2005 to 26% in 2009, together with an increase in the use of the posterior approach. The aim of this study was to determine whether rates of dislocation have fallen over the same period. National data for England for 247 546 procedures were analysed in order to determine trends in the rate of dislocation at three, six, 12 and 18 months after operation during this time. The 18-month revision rates were also examined. Between 2005 and 2009 there were significant decreases in cumulative dislocations at three months (1.12% to 0.86%), six months (1.25% to 0.96%) and 12 months (1.42% to 1.11%) (all p < 0.001), and at 18 months (1.56% to 1.31%) for the period 2005 to 2008 (p < 0.001). The 18-month revision rates did not significantly change during the study period (1.26% to 1.39%, odds ratio 1.10 (95% confidence interval 0.98 to 1.24), p = 0.118). There was no evidence of changes in the coding of dislocations during this time. These data have revealed a significant reduction in dislocations associated with the use of large femoral head sizes, with no change in the 18-month revision rate.
Biochemistry. Aug, 2011 | Pubmed ID: 21711014
The continual bacterial adaptation to antibiotics creates an ongoing medical need for the development of novel therapeutics. Polypeptide deformylase (PDF) is a highly conserved bacterial enzyme, which is essential for viability. It has previously been shown that PDF inhibitors represent a promising new area for the development of antimicrobial agents, and that many of the best PDF inhibitors demonstrate slow, time-dependent binding. To improve our understanding of the mechanistic origin of this time-dependent inhibition, we examined in detail the kinetics of PDF catalysis and inhibition by several different PDF inhibitors. Varying pH and solvent isotope led to clear changes in time-dependent inhibition parameters, as did inclusion of NaCl, which binds to the active site metal of PDF. Quantitative analysis of these results demonstrated that the observed time dependence arises from slow binding of the inhibitors to the active site metal. However, we also found several metal binding inhibitors that exhibited rapid, non-time-dependent onset of inhibition. By a combination of structural and chemical modification studies, we show that metal binding is only slow when the rest of the inhibitor makes optimal hydrogen bonds within the subsites of PDF. Both of these interactions between the inhibitor and enzyme were found to be necessary to observe time-dependent inhibition, as elimination of either leads to its loss.
Biophysical Journal. Jul, 2011 | Pubmed ID: 21723812
The collagen microstructure of the peripheral cornea is important in stabilizing corneal curvature and refractive status. However, the manner in which the predominantly orthogonal collagen fibrils of the central cornea integrate with the circumferential limbal collagen is unknown. We used microfocus wide-angle x-ray scattering to quantify the relative proportion and orientation of collagen fibrils over the human corneolimbal interface at intervals of 50 μm. Orthogonal fibrils changed direction 1-1.5 mm before the limbus to integrate with the circumferential limbal fibrils. Outside the central 6 mm, additional preferentially aligned collagen was found to reinforce the cornea and limbus. The manner of integration and degree of reinforcement varied significantly depending on the direction along which the limbus was approached. We also employed small-angle x-ray scattering to measure the average collagen fibril diameter from central cornea to limbus at 0.5 mm intervals. Fibril diameter was constant across the central 6 mm. More peripherally, fibril diameter increased, indicative of a merging of corneal and scleral collagen. The point of increase varied with direction, consistent with a scheme in which the oblique corneal periphery is reinforced by chords of scleral collagen. The results have implications for the cornea's biomechanical response to ocular surgeries involving peripheral incision.
Large Proteoglycan Complexes and Disturbed Collagen Architecture in the Corneal Extracellular Matrix of Mucopolysaccharidosis Type VII (Sly Syndrome)
Investigative Ophthalmology & Visual Science. Aug, 2011 | Pubmed ID: 21743015
Deficiencies in enzymes involved in proteoglycan (PG) turnover underlie a number of rare mucopolysaccharidoses (MPS), investigations of which can considerably aid understanding of the roles of PGs in corneal matrix biology. Here, the authors analyze novel pathologic changes in MPS VII (Sly syndrome) to determine the nature of PG-collagen associations in stromal ultrastructure.
Unusual Association of ST-T Abnormalities, Myocarditis and Cardiomyopathy with H1N1 Influenza in Pregnancy: Two Case Reports and Review of the Literature
Journal of Medical Case Reports. 2011 | Pubmed ID: 21756329
PloS One. 2011 | Pubmed ID: 21765897
Understanding the role of genetic variation in human diseases remains an important problem to be solved in genomics. An important component of such variation consist of variations at single sites in DNA, or single nucleotide polymorphisms (SNPs). Typically, the problem of associating particular SNPs to phenotypes has been confounded by hidden factors such as the presence of population structure, family structure or cryptic relatedness in the sample of individuals being analyzed. Such confounding factors lead to a large number of spurious associations and missed associations. Various statistical methods have been proposed to account for such confounding factors such as linear mixed-effect models (LMMs) or methods that adjust data based on a principal components analysis (PCA), but these methods either suffer from low power or cease to be tractable for larger numbers of individuals in the sample. Here we present a statistical model for conducting genome-wide association studies (GWAS) that accounts for such confounding factors. Our method scales in runtime quadratic in the number of individuals being studied with only a modest loss in statistical power as compared to LMM-based and PCA-based methods when testing on synthetic data that was generated from a generalized LMM. Applying our method to both real and synthetic human genotype/phenotype data, we demonstrate the ability of our model to correct for confounding factors while requiring significantly less runtime relative to LMMs. We have implemented methods for fitting these models, which are available at http://www.microsoft.com/science.
A Randomised Study of Peri-prosthetic Bone Density After Cemented Versus Trabecular Fixation of a Polyethylene Acetabular Component
The Journal of Bone and Joint Surgery. British Volume. Aug, 2011 | Pubmed ID: 21768625
The ideal acetabular component is characterised by reliable, long-term fixation with physiological loading of bone and a low rate of wear. Trabecular metal is a porous construct of tantalum which promotes bony ingrowth, has a modulus of elasticity similar to that of cancellous bone, and should be an excellent material for fixation. Between 2004 and 2006, 55 patients were randomised to receive either a cemented polyethylene or a monobloc trabecular metal acetabular component with a polyethylene articular surface. We measured the peri-prosthetic bone density around the acetabular components for up to two years using dual-energy x-ray absorptiometry. We found evidence that the cemented acetabular component loaded the acetabular bone centromedially whereas the trabecular metal monobloc loaded the lateral rim and behaved like a hemispherical rigid metal component with regard to loading of the acetabular bone. We suspect that this was due to the peripheral titanium rim used for the mechanism of insertion.
Molecular and Cellular Biochemistry. Oct, 2011 | Pubmed ID: 21769452
Protein kinase CK2 has many established in vitro substrates, but it is only within the past few years that we have begun to ascertain which of these are its real physiological targets, how their phosphorylation may contribute towards regulating normal cell physiology, and how phosphorylation of these proteins might influence the development of diseases such as cancer. One of the well-characterised in vitro substrates for CK2 is the tumour suppressor protein, p53. However, the physiological nature of this interaction has never been fully established. In the present article, we summarise a recent study from our laboratory showing that phosphorylation of p53 at Ser392, the sole site modified by CK2 in vitro, is regulated by a novel mechanism where the stoichiometry of phosphorylation is governed by the rate of turnover of the p53 protein. Such a model is entirely consistent with phosphorylation by a constitutively active protein kinase such as CK2. In contrast to this, while there is overwhelming evidence that CK2 phosphorylates p53 in vitro and is the only detectable Ser392 protein kinase in cell extracts, our data raise uncertainty as to whether this interaction truly reflects events underpinning Ser392 phosphorylation in vivo. We consider the possible role of CK2 in regulating the p53 response in a wider context and suggest key issues that should be addressed experimentally to provide a more cohesive picture of the relationship between this important protein kinase and a pivotal anti-cancer surveillance system in cells.
Physical Chemistry Chemical Physics : PCCP. Nov, 2011 | Pubmed ID: 21779581
Focusing optics for neutral molecules finds application in shaping and steering molecular beams. Here we present an electrostatic elliptical mirror for polar molecules consisting of an array of microstructured gold electrodes deposited on a glass substrate. Alternating positive and negative voltages applied to the electrodes create a repulsive potential for molecules in low-field-seeking states. The equipotential lines are parallel to the substrate surface, which is bent in an elliptical shape. The mirror is characterized by focusing a beam of metastable CO molecules and the results are compared to the outcome of trajectory simulations.
Efficacy of Increasing Dosages of Clarithromycin for Treatment of Experimental Mycoplasma Pneumoniae Pneumonia
The Journal of Antimicrobial Chemotherapy. Oct, 2011 | Pubmed ID: 21791441
Mycoplasma pneumoniae respiratory infection is a common cause of acute respiratory infection in children and adults. We evaluated the efficacy of increasing dosages of clarithromycin for the optimized therapy of M. pneumoniae respiratory infection in a mouse model.
Expression of Angiogenic Regulators and Skeletal Muscle Capillarity in Selectively Bred High Aerobic Capacity Mice
Experimental Physiology. Nov, 2011 | Pubmed ID: 21804139
Selective breeding for high voluntary wheel running in untrained mice has resulted in a 'mini muscle' (MM) phenotype, which has increased skeletal muscle capillarity compared with muscles from non-selected control lines. Vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) are essential mediators of skeletal muscle angiogenesis; thus, we hypothesized that untrained MM mice with elevated muscle capillarity would have higher basal VEGF expression and lower basal TSP-1 expression, and potentially an exaggerated VEGF response to acute exercise. We examined skeletal muscle morphology and skeletal muscle protein expression of VEGF and TSP-1 in male mice from two (untrained) mouse lines selectively bred for high exercise capacity (MM and Non-MM), as well as one non-selected control mouse line (normal aerobic capacity). In the MM mice, gastrocnemius (GA) and plantaris (PLT) muscle capillarity (i.e. capillary-to-fibre ratio and capillary density) were greater compared with control mice (P < 0.05). In Non-MM mice, only muscle capillarity in PLT was greater than in control mice (P < 0.001). The soleus (SOL) showed no statistical differences in muscle capillarity among groups. In the GA, MM mice had 58% greater basal VEGF (P < 0.05), with no statistical difference in basal TSP-1 when compared with control mice. In the PLT, MM mice had a 79% increase in basal VEGF (P < 0.05) and a 39% lower basal TSP-1 (P < 0.05) compared with the control animals. Non-MM mice showed no difference in basal VEGF in either the GA or the PLT compared with control mice. In contrast, basal TSP-1 was elevated in the PLT, but not in the GA, of Non-MM mice compared with control mice. Neither VEGF nor TSP-1 was significantly different in SOL muscle among the three mouse lines. In response to acute exercise, MM mice displayed a 41 and 28% increase (P < 0.05) in VEGF in the GA and PLT, respectively, whereas neither control nor Non-MM mice showed a significant VEGF response to acute exercise. In contrast, TSP-1 levels were decreased by 90% in GA (P < 0.05) but increased by 50% in PLT (P < 0.05) in response to acute exercise in MM mice. The SOL showed no response to exercise for either VEGF or TSP-1 for any of the mouse lines. These data, with the exception of the Non-MM plantaris muscle, suggest that elevated capillarity is associated with altered balance between positive and negative angiogenic regulators (i.e. VEGF versus TSP-1, respectively). Based on the greater capillarity and significant VEGF response to exercise in MM mice, these data suggest that VEGF expression may, at least in part, be genetically determined.
Biomaterials. Oct, 2011 | Pubmed ID: 21820172
Functionalisation of the surface of orthopaedic implants with nanotopographies that could stimulate in situ osteogenic differentiation of the patient's stem or osteoprogenitor cells would have significant therapeutic potential. Mesenchymal stem cell (MSC) responses to titanium substrates patterned with nanopillar structures were investigated in this study. Focal adhesions were quantified in S-phase cells, the bone-related transcription factor Runx2 was examined, osteocalcin production was noted, and Haralick computational analysis was used to assess the relatedness of the cell responses to each of the titanium substrata based on cytoskeletal textural features. Metabolomics was used as a novel means of assessing cellular responses to the biomaterial substrates by analysing the global metabolite profile of the cells on the substrata, and shows promise as a technique with high data yield for evaluating cell interactions with materials of different surface chemistry or topography. The cell response to 15 nm high nanopillars was distinct, consistent with a transition from a more quiescent phenotype on the planar substrate, to an 'active' phenotype on the pillars. These studies illustrate the potential for clinically relevant titania nanopillared substrata to modulate MSCs, with implications for orthopaedic device design and application.
Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation. Nov, 2011 | Pubmed ID: 21826515
We present the case of a 75-year-old woman with a medical history of rheumatoid arthritis treated with hydroxychloroquine, who was admitted with acute left-sided heart failure due to a hydroxychloroquine-induced cardiomyopathy as supported by endomyocardial biopsy.
Random Blood Glucose Measurement at Antenatal Booking to Screen for Overt Diabetes in Pregnancy: a Retrospective Study
Diabetes Care. Oct, 2011 | Pubmed ID: 21844290
To assess random venous blood glucose (RBG) measurement at antenatal booking to detect "overt diabetes in pregnancy" (ODIP).
PloS One. 2011 | Pubmed ID: 21850225
To determine the effect of Ultraviolet-A collagen cross-linking with hypo-osmolar and iso-osmolar riboflavin solutions on stromal collagen ultrastructure in normal and keratoconus ex vivo human corneas.
Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association. Dec, 2011 | Pubmed ID: 21854735
Opioids are sometimes used to treat chronic abdominal pain. However, opioid analgesics have not been proven to be an effective treatment for chronic abdominal pain and have been associated with drug misuse, constipation, and worsening abdominal pain. We sought to estimate the national prescribing trends and factors associated with opioid prescribing for chronic abdominal pain.
Object Discrimination with an Artificial Hand Using Electrical Stimulation of Peripheral Tactile and Proprioceptive Pathways with Intrafascicular Electrodes
IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. Oct, 2011 | Pubmed ID: 21859607
Trans-radial amputee subjects were implanted with intrafascicular electrodes in the stumps of the median and ulnar nerves. Electrical stimulation through these electrodes was used to provide sensations of touch and finger position referred to the amputated hand. Two subjects were asked to identify different objects as to size and stiffness by manipulating them with a myo-electric hand without visual or auditory cues. Both subjects were provided with information about contact force with the objects via tactile sensations referred to their phantom hands. One subject, who was provided with information about finger position in the prosthetic hand via a different tactile sensation referred to his phantom hand, was unable to correctly identify the objects. The other subject, who received information about finger position via a proprioceptive sensation referred to his phantom hand, correctly identified the objects at a level statistically significantly above chance performance.
Pharmacokinetic Mismatch Does Not Lead to Emergence of Isoniazid- or Rifampin-resistant Mycobacterium Tuberculosis but to Better Antimicrobial Effect: a New Paradigm for Antituberculosis Drug Scheduling
Antimicrobial Agents and Chemotherapy. Nov, 2011 | Pubmed ID: 21896907
Multidrug resistant-tuberculosis is a pressing problem. One of the major mechanisms proposed to lead to the emergence of drug resistance is pharmacokinetic mismatch. Stated as a falsifiable hypothesis, the greater the pharmacokinetic mismatch between rifampin and isoniazid, the higher the isoniazid- and rifampin-resistant subpopulation sizes become with time. To test this, we performed hollow-fiber-system studies for both bactericidal and sterilizing effects in experiments of up to 42 days. We mimicked pharmacokinetics of 600-mg/day rifampin and 300-mg/day isoniazid administered to patients. Rifampin was administered first, followed by isoniazid 0, 6, 12, and 24 h later. The treatment was for drug-susceptible Mycobacterium tuberculosis in some experiments and hollow fiber systems with inoculum preseeded with isoniazid- and rifampin-resistant isogenic Mycobacterium tuberculosis strains in others. Analysis of variance revealed that the 12-h and 24-h-mismatched regimens always killed better than the matched regimens during both bactericidal and sterilizing effects (P < 0.05). This means that either the order of scheduling or the sequential administration of drugs in combination therapy may lead to significant improvement in microbial killing. Rifampin-resistant and isoniazid-resistant subpopulations were not significantly higher with increased mismatching in numerous analysis-of-variance comparisons. Thus, the pharmacokinetic mismatch hypothesis was rejected. Instead, sequential administration of anti-tuberculosis (TB) drugs (i.e., deliberate mismatch) following particular schedules suggests a new paradigm for accelerating M. tuberculosis killing. We conclude that current efforts aimed at better pharmacokinetic matching to decrease M. tuberculosis resistance emergence are likely futile and counterproductive.
A Shift in Sensory Processing That Enables the Developing Human Brain to Discriminate Touch from Pain
Current Biology : CB. Sep, 2011 | Pubmed ID: 21906948
When and how infants begin to discriminate noxious from innocuous stimuli is a fundamental question in neuroscience . However, little is known about the development of the necessary cortical somatosensory functional prerequisites in the intact human brain. Recent studies of developing brain networks have emphasized the importance of transient spontaneous and evoked neuronal bursting activity in the formation of functional circuits [2, 3]. These neuronal bursts are present during development and precede the onset of sensory functions [4, 5]. Their disappearance and the emergence of more adult-like activity are therefore thought to signal the maturation of functional brain circuitry [2, 4]. Here we show the changing patterns of neuronal activity that underlie the onset of nociception and touch discrimination in the preterm infant. We have conducted noninvasive electroencephalogram (EEG) recording of the brain neuronal activity in response to time-locked touches and clinically essential noxious lances of the heel in infants aged 28-45 weeks gestation. We show a transition in brain response following tactile and noxious stimulation from nonspecific, evenly dispersed neuronal bursts to modality-specific, localized, evoked potentials. The results suggest that specific neural circuits necessary for discrimination between touch and nociception emerge from 35-37 weeks gestation in the human brain.
Hip International : the Journal of Clinical and Experimental Research on Hip Pathology and Therapy. Sep, 2011 | Pubmed ID: 21948033
The 'cement in cement' technique for revision hip arthroplasty has become popular in recent years, particularly in relation to polished taper stems. Since 2006 a short Exeter stem with 44 mm offset has been available specifically for this purpose. We report a fracture of such a stem in the absence of trauma 5 years after the revision procedure. The patient had a BMI of 27.8 and the proximal cement mantle gave good support to the stem. The fracture initiated and propagated from the introducer hole on the shoulder of the prosthesis. Macroscopically there was no defect in this area. This may be an unusual case of fatigue failure.
Inhibition of Homologous Recombination by DNA-dependent Protein Kinase Requires Kinase Activity, is Titratable, and is Modulated by Autophosphorylation
Molecular and Cellular Biology. Apr, 2011 | Pubmed ID: 21300785
How a cell chooses between nonhomologous end joining (NHEJ) and homologous recombination (HR) to repair a double-strand break (DSB) is a central and largely unanswered question. Although there is evidence of competition between HR and NHEJ, because of the DNA-dependent protein kinase (DNA-PK)'s cellular abundance, it seems that there must be more to the repair pathway choice than direct competition. Both a mutational approach and chemical inhibition were utilized to address how DNA-PK affects HR. We find that DNA-PK's ability to repress HR is both titratable and entirely dependent on its enzymatic activity. Still, although requisite, robust enzymatic activity is not sufficient to inhibit HR. Emerging data (including the data presented here) document the functional complexities of DNA-PK's extensive phosphorylations that likely occur on more than 40 sites. Even more, we show here that certain phosphorylations of the DNA-PK large catalytic subunit (DNA-PKcs) clearly promote HR while inhibiting NHEJ, and we conclude that the phosphorylation status of DNA-PK impacts how a cell chooses to repair a DSB.
The EMBO Journal. Mar, 2011 | Pubmed ID: 21317870
DNA non-homologous end joining (NHEJ) and homologous recombination (HR) function to repair DNA double-strand breaks (DSBs) in G2 phase with HR preferentially repairing heterochromatin-associated DSBs (HC-DSBs). Here, we examine the regulation of repair pathway usage at two-ended DSBs in G2. We identify the speed of DSB repair as a major component influencing repair pathway usage showing that DNA damage and chromatin complexity are factors influencing DSB repair rate and pathway choice. Loss of NHEJ proteins also slows DSB repair allowing increased resection. However, expression of an autophosphorylation-defective DNA-PKcs mutant, which binds DSBs but precludes the completion of NHEJ, dramatically reduces DSB end resection at all DSBs. In contrast, loss of HR does not impair repair by NHEJ although CtIP-dependent end resection precludes NHEJ usage. We propose that NHEJ initially attempts to repair DSBs and, if rapid rejoining does not ensue, then resection occurs promoting repair by HR. Finally, we identify novel roles for ATM in regulating DSB end resection; an indirect role in promoting KAP-1-dependent chromatin relaxation and a direct role in phosphorylating and activating CtIP.
BMC Immunology. 2011 | Pubmed ID: 21332988
Haplo-identical hematopoietic stem cell (HSC) transplantation is very successful in eradicating haematological tumours, but the long post-transplant T-lymphopenic phase is responsible for high morbidity and mortality rates. Clark et al. have described a skin-explant system capable of producing host-tolerant donor-HSC derived T-cells. Because this T-cell production platform has the potential to replenish the T-cell levels following transplantation, we set out to validate the skin-explant system.
Journal of Adolescence. Oct, 2011 | Pubmed ID: 21334059
Drawing on the social psychological concept of possible selves, this study explores the future self concept of young fathers in prison. In considering life after release from prison, qualitative data relating to hoped-for, feared and expected possible selves was generated by 34 young fathers aged between 18 and 21 years. The most common categories of hoped-for and expected selves related to employment and parenting, whereas feared selves related predominantly to offending or a return to prison. The prevalence of possible selves relating to parenting suggests that parenthood is a key component of the representations of present and future identity of young fathers in prison. Findings are discussed in relation to the positive aspect of parenthood for young men in prison, parenting identities in the transition from custody to community, future research directions and the development of interventions targeting young fathers in prison.
Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry. Jul, 2011 | Pubmed ID: 21344604
Polar molecules in selected quantum states can be guided, decelerated, and trapped using electric fields created by microstructured electrodes on a chip. Herein we explore how transitions between two of these quantum states can be induced while the molecules are on the chip. We use CO (a(3) Π(1) , v=0) molecules, prepared in the J=1 rotational level, and induce the J=2←J=1 rotational transition with narrow-band sub-THz (mm-wave) radiation. First, the mm-wave source is characterized using CO molecules in a freely propagating molecular beam, and both Rabi cycling and rapid adiabatic passage are examined. Then we demonstrate that the mm-wave radiation can be coupled to CO molecules that are less than 50 μm above the chip. Finally, CO molecules are guided in the J=1 level to the center of the chip where they are pumped to the J=2 level, recaptured, and guided off the chip.
Mutation Research. Jun, 2011 | Pubmed ID: 21376743
DNA double-strand breaks are extremely harmful lesions that can lead to genomic instability and cell death if not properly repaired. There are at least three pathways that are responsible for repairing DNA double-strand breaks in mammalian cells: non-homologous end joining, homologous recombination and alternative non-homologous end joining. Here we review each of these three pathways with an emphasis on the role of the DNA-dependent protein kinase, a critical component of the non-homologous end joining pathway, in influencing which pathway is ultimately utilized for repair.
Supported Community Exercise in People with Long-term Neurological Conditions: a Phase II Randomized Controlled Trial
Clinical Rehabilitation. Jul, 2011 | Pubmed ID: 21382866
Adults with long-term neurological conditions have low levels of participation in physical activities and report many barriers to participation in exercise. This study examines the feasibility and safety of supporting community exercise for people with long-term neurological conditions using a physical activity support system.
Multiple-input Single-output Closed-loop Isometric Force Control Using Asynchronous Intrafascicular Multi-electrode Stimulation
IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. Jun, 2011 | Pubmed ID: 21385670
Although asynchronous intrafascicular multi-electrode stimulation (IFMS) can evoke fatigue-resistant muscle force, a priori determination of the necessary stimulation parameters for precise force production is not possible. This paper presents a proportionally-modulated, multiple-input single-output (MISO) controller that was designed and experimentally validated for real-time, closed-loop force-feedback control of asynchronous IFMS. Experiments were conducted on anesthetized felines with a Utah Slanted Electrode Array implanted in the sciatic nerve, either acutely or chronically ( n = 1 for each). Isometric forces were evoked in plantar-flexor muscles, and target forces consisted of up to 7 min of step, sinusoidal, and more complex time-varying trajectories. The controller was successful in evoking steps in force with time-to-peak of less than 0.45 s, steady-state ripple of less than 7% of the mean steady-state force, and near-zero steady-state error even in the presence of muscle fatigue, but with transient overshoot of near 20%. The controller was also successful in evoking target sinusoidal and complex time-varying force trajectories with amplitude error of less than 0.5 N and time delay of approximately 300 ms. This MISO control strategy can potentially be used to develop closed-loop asynchronous IFMS controllers for a wide variety of multi-electrode stimulation applications to restore lost motor function.
Functional Circuitry of a Unique Cerebellar Specialization: the Valvula Cerebelli of a Mormyrid Fish
Neuroscience. May, 2011 | Pubmed ID: 21414387
The valvula cerebelli of the mormyrid electric fish is a useful site for the study of cerebellar function. The valvula forms a part of the electrosensory-electromotor system of this fish, a system that offers many possibilities for the study of sensory-motor integration. The valvula also has a number of histological features not present in mammals which facilitate investigation of cerebellar circuitry and its plasticity. This initial study characterizes the basic physiology and pharmacology of cells in the valvula using an in vitro slice preparation. Intrinsic properties and synaptic responses of Purkinje cells and other cell types were examined. We found that Purkinje cells fire a small narrow Na(+) spike and a large broad Ca(2+) spike, generated in the axon initial segment and dendritic-soma region, respectively. Purkinje cells respond to parallel fiber inputs with graded excitatory postsynaptic potentials (EPSPs) and to climbing fiber inputs with all-or-none EPSPs. Efferent cells, Golgi cells, and deep stellate cells all fire a single type of large narrow spike and respond only to parallel fiber inputs. Both parallel fiber and climbing fiber responses in Purkinje cells appear to be entirely mediated by AMPA-type glutamate receptors, whereas parallel fiber responses in efferent cells and stellate cells include AMPA and NMDA components. In addition, a strong synaptic inhibition was uncovered in both Purkinje cells and efferent cells in response to the focal stimulation of parallel fibers. Dual cell recordings indicate that deep stellate cells contribute at least partially to this inhibition. We conclude that despite its unique histology, the local functional circuitry of the mormyrid valvula cerebelli is largely similar to that of the mammalian cerebellum. Thus, what is learned concerning the functioning of the mormyrid valvula cerebelli may be expected to be informative about cerebellar function in general.
A Novel Integrative Method for Analyzing Eye and Hand Behaviour During Reaching and Grasping in an MRI Environment
Behavior Research Methods. Jun, 2011 | Pubmed ID: 21424188
The development of noninvasive neuroimaging techniques, such as fMRI, has rapidly advanced our understanding of the neural systems underlying the integration of visual and motor information. However, the fMRI experimental design is restricted by several environmental elements, such as the presence of the magnetic field and the restricted view of the participant, making it difficult to monitor and measure behaviour. The present article describes a novel, specialized software package developed in our laboratory called Biometric Integration Recording and Analysis (BIRA). BIRA integrates video with kinematic data derived from the hand and eye, acquired using MRI-compatible equipment. The present article demonstrates the acquisition and analysis of eye and hand data using BIRA in a mock (0 Tesla) scanner. A method for collecting and integrating gaze and kinematic data in fMRI studies on visuomotor behaviour has several advantages: Specifically, it will allow for more sophisticated, behaviourally driven analyses and eliminate potential confounds of gaze or kinematic data.
Journal of Pain and Symptom Management. Jul, 2011 | Pubmed ID: 21429701
With better antiretroviral treatments (ARTs), persons living with HIV (PLWH) are living longer, healthier lives. Therefore, they also experience more medical comorbidities that come with normal aging, as well as side effects of multiple treatments and long-term sequelae of HIV. It can be hard to know whether symptoms reported by PLWH are related to comorbidities or are signs of HIV disease progression and possible treatment failure.
Nature. Mar, 2011 | Pubmed ID: 21430774
Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant KRN7000.
Acta Ophthalmologica. Aug, 2011 | Pubmed ID: 21457485
The purpose of this study was to compare measurements of corneal hysteresis (CH) obtained in vivo, with similar measurements from excised human eyes and from excised human corneas mounted in an artificial anterior chamber.
Clinical, Environmental, and Genetic Determinants of Multiple Sclerosis in Children with Acute Demyelination: a Prospective National Cohort Study
Lancet Neurology. May, 2011 | Pubmed ID: 21459044
HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children.
Regulatory Toxicology and Pharmacology : RTP. Apr, 2011 | Pubmed ID: 21466831
This paper describes a framework for the risk assessment of combined exposure to multiple chemicals based on and developed subsequent to the World Health Organization/International Programme on Chemical Safety Workshop on Aggregate/Cumulative Risk Assessment (Combined Exposures to Multiple Chemicals) held in 2007. The framework is designed to aid risk assessors in identifying priorities for risk management for a wide range of applications where co-exposures to multiple chemicals are expected. It is based on a hierarchical (phased) approach that involves integrated and iterative consideration of exposure and hazard at all phases, with each tier being more refined (i.e., less cautious and more certain) than the previous one, but more labor and data intensive. It includes reference to predictive and probabilistic methodology in various tiers in addition to tiered consideration of uncertainty. The paper also annexes two case studies that have been developed to test and refine the framework.
Treatment and Assessment of Emergency Department Nausea and Vomiting in Australasia: a Survey of Anti-emetic Management
Emergency Medicine Australasia : EMA. Apr, 2011 | Pubmed ID: 21489163
To describe the treatment and assessment of emergency department nausea and vomiting (EDNV) in Australasia by Fellows of the Australasian College for Emergency Medicine (FACEM). To determine the influence of various factors on FACEM anti-emetic choice. To compare the influence of drug effectiveness, side effects, cost and pharmacy directives on adult EDNV anti-emetic choice between FACEM choosing the two most common first-line agents.
Seasonal and 2009 Pandemic Influenza A (H1N1) Virus Infection During Pregnancy: a Population-based Study of Hospitalized Cases
American Journal of Obstetrics and Gynecology. Jun, 2011 | Pubmed ID: 21507375
We sought to describe characteristics of hospitalized reproductive-aged (15-44 years) women with seasonal (2005/2006 through 2008/2009) and 2009 pandemic influenza A (H1N1) virus infection. We used population-based data from the Emerging Infections Program in 10 US states, and compared characteristics of pregnant (n = 150) and nonpregnant (n = 489) seasonal, and pregnant (n = 489) and nonpregnant (n = 1088) pandemic influenza cases using χ(2) and Fisher's exact tests. Pregnant women represented 23.5% and 31.0% of all reproductive-aged women hospitalized for seasonal and pandemic influenza, respectively. Significantly more nonpregnant than pregnant women with seasonal (71.2% vs 36.0%) and pandemic (69.7% vs 31.9%) influenza had an underlying medical condition other than pregnancy. Antiviral treatment was significantly more common with pandemic than seasonal influenza for both pregnant (86.5% vs 24.0%) and nonpregnant (82.0% vs 55.2%) women. Pregnant women comprised a significant proportion of influenza-hospitalized reproductive-aged women, underscoring the importance of influenza vaccination during pregnancy.
Infectious Diseases in Obstetrics and Gynecology. 2011 | Pubmed ID: 21603233
This prospective study was undertaken to evaluate pregnant women's willingness to undergo HSV type-specific serologic testing and factors affecting willingness in an obstetrics/gynecology ambulatory unit.
Clinical Chemistry. Jun, 2011 | Pubmed ID: 21622923
Pediatrics. Jul, 2011 | Pubmed ID: 21646257
To describe the characteristics and clinical courses of asthmatic children hospitalized with seasonal or 2009 pandemic H1N1 influenza and compare complications by influenza type.
Nursing Administration Quarterly. Jul-Sep, 2011 | Pubmed ID: 21654484
The changing framework of today's health care system requires leaders to be increasingly innovative in how they approach their daily functions and responsibilities. Sustaining and advancing a level of innovation that already exists can be challenging for health care administrators with the demands of time and resource limitations. Using collaboration to bring new-age teaching and disciplines to front-line leadership, one hospital was able to reinvigorate a culture of innovation through multiple levels and disciplines of the organization. The Innovation Certification Course provided nursing leaders and other managers' an evidence-drive approach, new principles and useful strategies of innovative leadership and graduate program education.
Glucose Meters and Opportunities for In-hospital Transmission of Infection: Quantitative Assessment and Management with and Without Patient Assignment
American Journal of Infection Control. Nov, 2011 | Pubmed ID: 21700364
Increasing use of glucose meters in hospitals has increased opportunities for infection transmission that have not been quantitatively assessed or managed.
The Biological Control of Voluntary Exercise, Spontaneous Physical Activity and Daily Energy Expenditure in Relation to Obesity: Human and Rodent Perspectives
The Journal of Experimental Biology. Jan, 2011 | Pubmed ID: 21177942
Mammals expend energy in many ways, including basic cellular maintenance and repair, digestion, thermoregulation, locomotion, growth and reproduction. These processes can vary tremendously among species and individuals, potentially leading to large variation in daily energy expenditure (DEE). Locomotor energy costs can be substantial for large-bodied species and those with high-activity lifestyles. For humans in industrialized societies, locomotion necessary for daily activities is often relatively low, so it has been presumed that activity energy expenditure and DEE are lower than in our ancestors. Whether this is true and has contributed to a rise in obesity is controversial. In humans, much attention has centered on spontaneous physical activity (SPA) or non-exercise activity thermogenesis (NEAT), the latter sometimes defined so broadly as to include all energy expended due to activity, exclusive of volitional exercise. Given that most people in Western societies engage in little voluntary exercise, increasing NEAT may be an effective way to maintain DEE and combat overweight and obesity. One way to promote NEAT is to decrease the amount of time spent on sedentary behaviours (e.g. watching television). The effects of voluntary exercise on other components of physical activity are highly variable in humans, partly as a function of age, and have rarely been studied in rodents. However, most rodent studies indicate that food consumption increases in the presence of wheels; therefore, other aspects of physical activity are not reduced enough to compensate for the energetic cost of wheel running. Most rodent studies also show negative effects of wheel access on body fat, especially in males. Sedentary behaviours per se have not been studied in rodents in relation to obesity. Several lines of evidence demonstrate the important role of dopamine, in addition to other neural signaling networks (e.g. the endocannabinoid system), in the control of voluntary exercise. A largely separate literature points to a key role for orexins in SPA and NEAT. Brain reward centers are involved in both types of physical activities and eating behaviours, likely leading to complex interactions. Moreover, voluntary exercise and, possibly, eating can be addictive. A growing body of research considers the relationships between personality traits and physical activity, appetite, obesity and other aspects of physical and mental health. Future studies should explore the neurobiology, endocrinology and genetics of physical activity and sedentary behaviour by examining key brain areas, neurotransmitters and hormones involved in motivation, reward and/or the regulation of energy balance.
Adhesion of Laser in Situ Keratomileusis-like Flaps in the Cornea: Effects of Crosslinking, Stromal Fibroblasts, and Cytokine Treatment
Journal of Cataract and Refractive Surgery. Jan, 2011 | Pubmed ID: 21183111
To evaluate 3 approaches, both cellular and acellular, to improve the healing of laser in situ keratomileusis flaps in bovine corneas.
Behavior Genetics. Jul, 2011 | Pubmed ID: 21184162
When populations with similar histories of directional selection are crossed, their offspring may differ in mean phenotype as compared with the average for the parental populations, often exhibiting enhancement of the mean phenotype (termed heterosis or hybrid vigor). We tested for heterosis in a cross of two replicate lines of mice selectively bred for high voluntary wheel running for 53 generations. Mice were paired to produce four sets of F1 offspring: two purebred High Runner (HR) lines and the hybrid reciprocal crosses. The purebred HR showed statistically significant, sex-dependent differences in body mass, wheel revolutions, running duration, mean running speed, and (controlling for body mass) organ masses (heart ventricles, liver, spleen, triceps surae muscle). Hybrid males ran significantly more revolutions than the purebred males, mainly via increased running speeds, but hybrid females ran intermediate distances, durations, and speeds, as compared with the purebred females. In both sexes, ventricles were relatively smaller in hybrids as compared with purebred HR. Overall, our results demonstrate differential and sex-specific responses to selection in the two HR lines tested, implying divergent genetic architectures underlying high voluntary exercise.
The Journal of Bone and Joint Surgery. British Volume. Jan, 2011 | Pubmed ID: 21196551
Peri-prosthetic fracture after joint replacement in the lower limb is associated with significant morbidity. The primary aim of this study was to investigate the incidence of peri-prosthetic fracture after total hip replacement (THR) and total knee replacement (TKR) over a ten-year period using a population-based linked dataset. Between 1 April 1997 and 31 March 2008, 52,136 primary THRs, 8726 revision THRs, 44,511 primary TKRs, and 3222 revision TKRs were performed. Five years post-operatively, the rate of fracture was 0.9% after primary THR, 4.2% after revision THR, 0.6% after primary TKR and 1.7% after revision TKR. Comparison of survival analysis for all primary and revision arthroplasties showed peri-prosthetic fractures were more likely in females, patients aged > 70 and after revision arthroplasty. Female patients aged > 70 should be warned of a significantly increased risk of peri-prosthetic fracture after hip or knee replacement. The use of adjuvant medical treatment to reduce the effect of peri-prosthetic osteoporosis may be a direction of research for these patients.
The Use of Modular Femoral Head Trials to Centre the Explant Blade Facilitates Retrieval of Well-fixed Acetabular Components with Minimal Bone Loss
Archives of Orthopaedic and Trauma Surgery. Jul, 2011 | Pubmed ID: 21221612
The Zimmer-Explant system has made removal of a well-fixed monobloc acetabular component less challenging, but depends on the presence of an intact liner for instrument centralization. We report the outcome of 15 hips with well-fixed, cementless resurfacing sockets, which were removed using a modification of the existing method. We conclude that the existing Explant system combined with modular trial heads allows safe removal of monobloc shells with minimal bone loss.
Critical Reviews in Toxicology. Jan, 2011 | Pubmed ID: 21226629
The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic endpoints should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general "additivity-to-background" argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties-properties that would not be expected for most noncancer effects. Second, the "heterogeneity in the population" argument states that variations in sensitivity among members of the target population tend to "flatten out and linearize" the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true nonthreshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed.
International Journal of Clinical Practice. Feb, 2011 | Pubmed ID: 21235694
Cardiovascular disease (CVD) is the most common cause of death worldwide. Pharmaceutical risk reduction with high-intensity statin therapy is advisable for high-risk patients. Clinicians face a conflict between prescribing for cost (simvastatin 80 mg) or for efficacy (atorvastatin 80 mg). The aim of this audit was to examine the use, efficacy and tolerability of high intensity statin treatment (simvastatin 80 mg; atorvastatin 80 mg) in primary care.
The Clinical Impact of Combining Intermittent Preventive Treatment with Home Management of Malaria in Children Aged Below 5 Years: Cluster Randomised Trial
Tropical Medicine & International Health : TM & IH. Mar, 2011 | Pubmed ID: 21159081
To investigate the impact of seasonal intermittent preventive treatment (IPTc) on malaria-related morbidity in children <5 years of age who already had access to home-based management of malaria (HMM) for presumptive treatment of fevers.
The Influence of Lamellar Orientation on Corneal Material Behavior: Biomechanical and Structural Changes in an Avian Corneal Disorder
Investigative Ophthalmology & Visual Science. Mar, 2011 | Pubmed ID: 21051696
Retinopathy, globe enlarged (RGE) is an inherited genetic disease of chickens with a corneal phenotype characterized by loss of tissue curvature and changes in peripheral collagen fibril alignment. This study aimed to characterize the material behavior of normal and RGE chicken corneas under inflation and compare this with new spatial- and depth-resolved microstructural information to investigate how stromal fibril architecture determines corneal behavior under intraocular pressure (IOP).
Development and Validation of an Instrument for Rapidly Assessing Symptoms: the General Symptom Distress Scale
Journal of Pain and Symptom Management. Mar, 2011 | Pubmed ID: 21131168
Symptom assessment has increasingly focused on the evaluation of total symptom distress or burden rather than assessing only individual symptoms. The challenge for clinicians and researchers alike is to assess symptoms, and to determine the symptom distress associated with the symptoms and the patient's ability for symptom management without a lengthy and burdensome assessment process.
Role of Keratan Sulphate (sulphated Poly -N-acetyllactosamine Repeats) in Keratoconic Cornea, Histochemical, and Ultrastructural Analysis
Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Für Klinische Und Experimentelle Ophthalmologie. Mar, 2011 | Pubmed ID: 20853116
Keratan sulphate (KS) is the predominant glycosaminoglycan (GAG) present in the corneal stroma where it is thought to regulate collagen fibril diameter. In this study we investigated the distribution of KS in normal and keratoconic corneas.
Advanced Materials (Deerfield Beach, Fla.). Jan, 2011 | Pubmed ID: 20972981
Metal-organic frameworks (MOFs) represent a new class of hybrid organic-inorganic supramolecular materials comprised of ordered networks formed from organic electron donor linkers and metal cations. They can exhibit extremely high surface areas, as well as tunable pore size and functionality, and can act as hosts for a variety of guest molecules. Since their discovery, MOFs have enjoyed extensive exploration, with applications ranging from gas storage to drug delivery to sensing. This review covers advances in the MOF field from the past three years, focusing on applications, including gas separation, catalysis, drug delivery, optical and electronic applications, and sensing. We also summarize recent work on methods for MOF synthesis and computational modeling.
Digestive Diseases and Sciences. Jan, 2011 | Pubmed ID: 20596778
Anticholinergic drugs are commonly prescribed for symptomatic treatment of overactive bladder (OAB). While recent meta-analyses have characterized the prevalence of dry mouth among patients utilizing OAB medications, prevalence of constipation has not been systematically reviewed.
The Review of Scientific Instruments. Sep, 2011 | Pubmed ID: 21974574
Recently, a decelerator for neutral polar molecules has been presented that operates on the basis of macroscopic, three-dimensional, traveling electrostatic traps [A. Osterwalder, S. A. Meek, G. Hammer, H. Haak, and G. Meijer, Phys. Rev. A 81, 051401 (2010)]. In the present paper, a complete description of this decelerator is given, with emphasis on the electronics and the mechanical design. Experimental results showing the transverse velocity distributions of guided molecules are shown and compared to trajectory simulations. An assessment of non-adiabatic losses is made by comparing the deceleration signals from (13)CO with those from (12)CO and with simulated signals.
Emerging Infectious Diseases. Oct, 2011 | Pubmed ID: 22000379
Clostridium difficile, the most commonly recognized diarrheagenic pathogen among hospitalized persons, can cause outpatient diarrhea. Of 1,091 outpatients with diarrhea, we found 43 (3.9%) who were positive for C. difficile toxin. Only 7 had no recognized risk factors, and 3 had neither risk factors nor co-infection with another enteric pathogen.
Placental Plasmodium Falciparum Malaria Infection: Operational Accuracy of HRP2 Rapid Diagnostic Tests in a Malaria Endemic Setting
Malaria Journal. 2011 | Pubmed ID: 22004666
Malaria has a negative effect on the outcome of pregnancy. Pregnant women are at high risk of severe malaria and severe haemolytic anaemia, which contribute 60-70% of foetal and perinatal losses. Peripheral blood smear microscopy under-estimates sequestered placental infections, therefore malaria rapid diagnostic tests (RDTs) detecting histidine rich protein-2 antigen (HRP-2) in peripheral blood are a potential alternative.
Multidrug-resistant Tuberculosis Not Due to Noncompliance but to Between-patient Pharmacokinetic Variability
The Journal of Infectious Diseases. Dec, 2011 | Pubmed ID: 22021624
It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis (MDR-tuberculosis) emergence. The level of nonadherence associated with emergence of MDR-tuberculosis is unknown. Performance of a randomized controlled trial in which some patients are randomized to nonadherence would be unethical; therefore, other study designs should be utilized.
An Interspecies Analysis Reveals a Key Role for Unmethylated CpG Dinucleotides in Vertebrate Polycomb Complex Recruitment
The EMBO Journal. 2011 | Pubmed ID: 22056776
The role of DNA sequence in determining chromatin state is incompletely understood. We have previously demonstrated that large chromosomal segments from human cells recapitulate their native chromatin state in mouse cells, but the relative contribution of local sequences versus their genomic context remains unknown. In this study, we compare orthologous chromosomal regions for which the human locus establishes prominent sites of Polycomb complex recruitment in pluripotent stem cells, whereas the corresponding mouse locus does not. Using recombination-mediated cassette exchange at the mouse locus, we establish the primacy of local sequences in the encoding of chromatin state. We show that the signal for chromatin bivalency is redundantly encoded across a bivalent domain and that this reflects competition between Polycomb complex recruitment and transcriptional activation. Furthermore, our results suggest that a high density of unmethylated CpG dinucleotides is sufficient for vertebrate Polycomb recruitment. This model is supported by analysis of DNA methyltransferase-deficient embryonic stem cells.
JEMS : a Journal of Emergency Medical Services. Nov, 2011 | Pubmed ID: 22061685
Pediatrics. Dec, 2011 | Pubmed ID: 22084328
Electronic immunization information systems (IISs) are now established in almost all US states. We used the IIS in Minnesota, Georgia, and Connecticut for immunization data and as the source of 1 of 2 control groups to measure pentavalent rotavirus vaccine (RV5) effectiveness (VE) using case-control methodology.
Techniques in Vascular and Interventional Radiology. Dec, 2011 | Pubmed ID: 22099013
This paper provides readers with a basic understanding of the types of central venous access-associated infections as well as appropriate diagnostic techniques. Preventive measures are the most effective way to reduce rates of catheter-associated infection and are discussed in detail. Diagnosis and treatment of each type of infection are reviewed for nontunneled central venous catheters, tunneled dialysis catheters, and venous access ports. Readers should be able to employ the methods described in this paper to reduce the rate of central venous access-associated infections at their hospitals.
Within-population Diversity of Koala Chlamydophila Pecorum at OmpA VD1-VD3 and the ORF663 Hypothetical Gene
Veterinary Microbiology. Nov, 2011 | Pubmed ID: 22118784
Infection of koalas by Chlamydophila pecorum is very common and causes significant morbidity, infertility and mortality. Fundamental to management of the disease is an understanding of the importance of multi-serotype infection or pathogen virulence in pathogenesis; these may need consideration in plans involving koala movement, vaccination, or disease risk assessment. Here we describe diversity of ompA VD1-3, and ORF663 hypothetical gene tandem repeat regions, in a single population of koalas with diverse disease outcomes. We PCR amplified and sequenced 72 partial ompA segments and amplified 25 tandem repeat segments (ORF663 hypothetical gene) from C. pecorum obtained from 62 koalas. Although several ompA genotypes were identified nationally, only one ompA genotype existed within the population studied, indicating that severe chlamydial disease occurs commonly in free-ranging koalas in the absence of infection by multiple MOMP serotypes of C. pecorum. In contrast, variation in tandem repeats within the ORF663 hypothetical gene was very high, approaching the entire range reported for pathogenic and non-pathogenic C. pecorum of European ruminants; providing an impetus for further investigation of this as a potential virulence trait.
Journal of Opioid Management. Sep-Oct, 2011 | Pubmed ID: 22165038
Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system. Neuropathic pain is composed of peripheral neuropathic pain (with a primary lesion or dysfunction in the peripheral nervous system) and central neuropathic pain (CNP; with a primary lesion or dysfunction in the central nervous system). CNP may be further subdivided into supraspinal central neuropathic pain and spinal central neuropathic pain. Opioids have a role in the pharmacologic management of neuropathic pain; however, there is a scarcity of literature on the treatment of CNP with opioids. One of the few statements in the literature regarding the analgesic efficacy of opioids for CNP suggests that despite limited data, the opioid responsiveness for neuropathic pain of central and peripheral etiologies is similar. After reviewing the extremely limited data, it is proposed that although there may be a subpopulation of patients with CNP who have a reasonable analgesic response to opioids, overall, when sensory pain rating is used as the yardstick, CNP appears to respond less well to opioids than peripheral neuropathic pain. Thus, opioids should be considered a second- or third-line agent in any algorithm of the pharmacologic treatment of CNP. Also within CAP, it appears that supraspinal central neuropathic pain may respond less well to a trial of opioids than spinal central neuropathic pain. Moreover, under close monitoring for side effects (eg, constipation), it is suggested that clinicians may want to consider titrating to higher doses of potent opioids before the trial is judged to be unsuccessful for refractory supraspinal central neuropathic pain.
Nursing New Zealand (Wellington, N.Z. : 1995). Oct, 2011 | Pubmed ID: 22165768
N-terminal Constraint Activates the Catalytic Subunit of the DNA-dependent Protein Kinase in the Absence of DNA or Ku
Nucleic Acids Research. Dec, 2011 | Pubmed ID: 22167471
The DNA-dependent protein kinase (DNA-PK) was identified as an activity and as its three component polypeptides 25 and 15 years ago, respectively. It has been exhaustively characterized as being absolutely dependent on free double stranded DNA ends (to which it is directed by its regulatory subunit, Ku) for its activation as a robust nuclear serine/threonine protein kinase. Here, we report the unexpected finding of robust DNA-PKcs activation by N-terminal constraint, independent of either DNA or its regulatory subunit Ku. These data suggest that an N-terminal conformational change (likely induced by DNA binding) induces enzymatic activation.
Pediatrics. Nov, 2011 | Pubmed ID: 22167859
Low Serum Iron Levels Are Associated with Elevated Plasma Levels of Coagulation Factor VIII and Pulmonary Emboli/deep Venous Thromboses in Replicate Cohorts of Patients with Hereditary Haemorrhagic Telangiectasia
Thorax. Dec, 2011 | Pubmed ID: 22169361
BackgroundElevated plasma levels of coagulation factor VIII are a strong risk factor for pulmonary emboli and deep venous thromboses.ObjectivesTo identify reversible biomarkers associated with high factor VIII and assess potential significance in a specific at-risk population.Patients/Methods609 patients with hereditary haemorrhagic telangiectasia were recruited prospectively in two separate series at a single centre. Associations between log-transformed factor VIII measured 6 months from any known thrombosis/illness, and patient-specific variables including markers of inflammation and iron deficiency, were assessed in stepwise multiple regression analyses. Age-specific incidence rates of radiologically proven pulmonary emboli/deep venous thromboses were calculated, and logistic regression analyses performed.ResultsIn each series, there was an inverse association between factor VIII and serum iron that persisted after adjustment for age, inflammation and/or von Willebrand factor. Iron response elements within untranslated regions of factor VIII transcripts provide potential mechanisms for the association. Low serum iron levels were also associated with venous thromboemboli (VTE): the age-adjusted OR of 0.91 (95% CI 0.86 to 0.97) per 1 μmol/litre increase in serum iron implied a 2.5-fold increase in VTE risk for a serum iron of 6 μmol/litre compared with the mid-normal range (17 μmol/litre). The association appeared to depend on factor VIII, as once adjusted for factor VIII, the association between VTE and iron was no longer evident.ConclusionsIn this population, low serum iron levels attributed to inadequate replacement of haemorrhagic iron losses are associated with elevated plasma levels of coagulation factor VIII and venous thromboembolic risk. Potential implications for other clinical populations are discussed.
Journal of Long-term Effects of Medical Implants. 2011 | Pubmed ID: 22150354
Acetabular introducers have a built-in inclination of 45 degrees to the handle shaft. With patients in the lateral position, surgeons aim to align the introducer shaft vertical to the floor to implant the acetabulum at 45 degrees. We aimed to determine if a bulls-eye spirit level attached to an introducer improved the accuracy of implantation. A small circular bulls-eye spirit level was attached to the handle of an acetabular introducer. A saw bone hemipelvis was fixed to a horizontal, flat surface. A cement substitute was placed in the acetabulum and subjects were asked to implant a polyethylene cup, aiming to obtain an angle of inclination of 45 degrees. Two attempts were made with the spirit level masked and two with it unmasked. The distance of the air bubble from the spirit level's center was recorded by a single assessor. The angle of inclination of the acetabular component was then calculated. Subjects included both orthopedic consultants and trainees. Twenty-five subjects completed the study. Accuracy of acetabular implantation when using the unmasked spirit level improved significantly in all grades of surgeon. With the spirit level masked, 12 out of 50 attempts were accurate at 45 degrees inclination; 11 out of 50 attempts were "open," with greater than 45 degrees of inclination, and 27 were "closed," with less than 45 degrees. With the spirit level visible, all subjects achieved an inclination angle of exactly 45 degrees. A simple device attached to the handle of an acetabular introducer can significantly improve the accuracy of implantation of a cemented cup into a saw bone pelvis in the lateral position.
The Effect of Vitamin C Deficiency and Chronic Ultraviolet-B Exposure on Corneal Ultrastructure: a Preliminary Investigation
Molecular Vision. 2011 | Pubmed ID: 22171156
In the visually debilitating condition of climatic droplet keratopathy, corneal transparency is progressively lost. Although the precise cause of the disease and the mechanism by which it progresses are not known, a lifetime exposure to high solar radiation and a vitamin C-deficient diet may be involved in its development. This study examines the effect of dietary ascorbate levels and ultraviolet (UV)-B exposure on corneal stromal structure.
Journal of Plastic Surgery and Hand Surgery. Dec, 2011 | Pubmed ID: 22250724
Abstract Macrodystrophia lipomatosa is a rare disease that causes congenital local gigantism of part of an extremity, which is characterised by an increase in all mesenchymal elements, particularly fibroadipose tissue. This is the first report to our knowledge of a case of histologically confirmed bilateral macrodystrophia lipomatosa of the upper extremities with syndactyly and multiple lipomas.
Journal of Plastic Surgery and Hand Surgery. Dec, 2011 | Pubmed ID: 22250725
Abstract Kienböck disease can be treated either conservatively or by various operations. We describe the findings of the progression of Kienböck disease over 60 years in an 84-year-old man who had had no surgical treatment. This is the longest follow-up ever reported to our knowledge of a patient with avascular necrosis of the lunate.
Daily and Intermittent Rosuvastatin 5 mg Therapy in Statin Intolerant Patients: an Observational Study
Current Medical Research and Opinion. Feb, 2012 | Pubmed ID: 22256801
Abstract Objective: To examine the efficacy and tolerability of rosuvastatin 5 mg at daily and non-daily dosing regimens. Research design and methods: A retrospective survey was conducted at nine primary, secondary and tertiary healthcare centres in the United Kingdom. Main outcome measures: Changes in lipid fractions from baseline values after more than 3 months' treatment. Results: A total of 325 patients were identified. These patients were aged 63 ± 10 years, 50% male and prescription was mostly for primary prevention of cardiovascular disease (CVD) (59%). Co-morbidities included: established CVD present in 41%, type 2 diabetes mellitus (15%), hypertension (74%) and smoking (9%). Adverse effects had been documented to simvastatin (75%) or atorvastatin (63%). A total of 289 patients (89%) tolerated rosuvastatin well and were still adherent after a median follow-up of 14.9 (3-79) months. The remainder (n = 36; 11%) discontinued the medication after median 5 months' treatment due to adverse effects. Efficacy was assessed in 224 patients who had adequate data. Baseline lipids were total cholesterol (TC) 7.41 ± 1.50 mmol/L, triglycerides (TG) 2.26 (range 0.36-18.4) mmol/L; high density lipoprotein cholesterol (HDL-C) 1.43 ± 0.47 mmol/L and low density lipoprotein cholesterol (LDL-C) 4.76 ± 1.38 mmol/L. Daily rosuvastatin (n = 134) reduced mean TC by 31%, TG 15% and LDL-C 43% (p < 0.001). Rosuvastatin 5 mg 2-3 times weekly (n = 79) reduced TC 26%, TG 16% and LDL-C 32% (p < 0.001). Weekly rosuvastatin (n = 11) reduced TC 17%, LDL-C by 23% (p < 0.001) but had no effect on TGs. Targets were attained in 17% of CHD-risk equivalent patients and 41% of primary prevention patients by National Cholesterol Education Program criteria and 27% and 68% using UK targets. No myositis or rhabdomyolysis was observed and alanine aminotransferase (ALT) and creatine kinase (CK) were similar to baseline. Conclusions: In this retrospective observational multicentre study, rosuvastatin 5 mg was found to be safe and biochemically effective either as daily or intermittent therapy in patients intolerant to other conventional statin regimens.
Chest. Jan, 2012 | Pubmed ID: 22267681
Abstract BACKGROUND:Most measures of dyspnea assess a single aspect (intensity or distress) of the symptom. We developed the Multidimensional Dyspnea Profile (MDP) to measure qualities and intensities of the sensory dimension and components of the affective dimension. The MDP is not indexed to a particular activity and can be applied at rest, during exertion, or clinical care. We report on the development and testing of the MDP in patients with a variety of acute and chronic cardiopulmonary conditions. METHODS:151 adults admitted to the emergency department (ED) with breathing complaints completed the MDP three times in the ED, twice at least 1 hour apart (T1, T2), and near discharge from the ED (T3). Measures were repeated in 68 patients twice in a follow-up session 4 to 6 weeks later (T4-T5). The ED sample was 56 % male with a mean age of 53 (±15 sd) years; the follow-up sample was similar. RESULTS:Factor analysis resulted in a two-factor solution with a total explained variance of 63%, 74% and 72% at T1, T2 and T3 respectively. One domain related to primary sensory qualities and immediate unpleasantness, the second encompassed emotional response. For the two domains Cronbach's α ranged from 0.82-0.95 and Intraclass Correlation Coefficient ranged from 0.91-0.98. Repeated measures analysis was significant for change (T1,T3,T4) showing responsiveness to change in MDP domains with treatment (F=19.67 [2,66] p>0.001). CONCLUSIONS:These analyses support the reliability, validity, and responsiveness to clinical change of the MDP with two domains in an acute care and follow-up setting.
Optimizing the Osteogenicity of Nanotopography Using Block Co-polymer Phase Separation Fabrication Techniques
Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society. Jan, 2012 | Pubmed ID: 22294345
Both temporary and permanent orthopedic implants have, by default or design, surface chemistry, and topography. There is increasing evidence that controlling nanodisorder can result in increased osteogenesis. Block co-polymer phase separation can be used to fabricate a nanotopography exhibiting a controlled level of disorder, both reproducibly and cost-effectively. Two different topographies, produced through the use of block co-polymer phase separation, were embossed onto the biodegradable thermoplastic, polycaprolactone (PCL). Analysis of the topography itself was undertaken with atomic force microscopy, and the topography's effect on human osteoblasts studied through the use of immunocytochemistry and fluorescence microscopy. Planar controls had a surface roughness 0.93 nm, and the substrates a high fidelity transfer of a disordered pattern of 14 and 18 nm. Cytoskeletal organization and adhesion, and increased expression of Runx2 were significantly greater on the smallest nanotopography. Expression of osteopontin and osteocalcin protein, and alizarin red staining of bone nodules were greatest on the smallest feature nanopatterns. Highly osteogenic, disordered nanotopographies can be manufactured into thermoplastics in a rapid and cost-effective way through the use of block co-polymer phase separation. Osteogenic topographies reproducibly and cost-effectively produced have a potentially useful application to the fields of implant technology and regenerative orthopedics. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
Chronic Respiratory Disease. 2012 | Pubmed ID: 22308551
Self-management is of increasing importance in chronic obstructive pulmonary disease (COPD) management. However, there is confusion over what processes are involved, how the value of self-management should be determined, and about the research priorities. To gain more insight into and agreement about the content of programmes, outcomes, and future directions of COPD self-management, a group of interested researchers and physicians, all of whom had previously published on this subject and who had previously collaborated on other projects, convened a workshop. This article summarises their initial findings. Self-management programmes aim at structural behaviour change to sustain treatment effects after programmes have been completed. The programmes should include techniques aimed at behavioural change, be tailored individually, take the patient's perspective into account, and may vary with the course of the patient's disease and co-morbidities. Assessment should include process variables. This report is a step towards greater conformity in the field of self-management. To enhance clarity regarding effectiveness, future studies should clearly describe their intervention, be properly designed and powered, and include outcomes that focus more on the acquisition and practice of new skills. In this way more evidence and a better comprehension on self-management programmes will be obtained, and more specific formulation of guidelines on self-management made possible.
Archives of Ophthalmology. Feb, 2012 | Pubmed ID: 22332225
An Official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea
American Journal of Respiratory and Critical Care Medicine. Feb, 2012 | Pubmed ID: 22336677
Background: Dyspnea is a common, distressing symptom of cardiopulmonary and neuromuscular diseases. Since the ATS published a consensus statement on dyspnea in 1999, there has been enormous growth in knowledge about the neurophysiology of dyspnea and increasing interest in dyspnea as a patient-reported outcome. Purpose: The purpose of this document is to update the 1999 ATS Consensus Statement on dyspnea. Methods: An interdisciplinary committee of experts representing ATS assemblies on Nursing, Clinical Problems, Sleep and Respiratory Neurobiology, Pulmonary Rehabilitation, and Behavioral Science determined the overall scope of this update through group consensus. Focused literature reviews in key topic areas were conducted by committee members with relevant expertise. The final content of this statement was agreed upon by all members. Results: Progress has been made in clarifying mechanisms underlying several qualitatively and mechanistically distinct breathing sensations. Brain imaging studies have consistently shown dyspnea stimuli to be correlated with activation of cortico-limbic areas involved with interoception and nociception. Endogenous and exogenous opioids may modulate perception of dyspnea. Instruments for measuring dyspnea are often poorly characterized; a framework is proposed for more consistent identification of measurement domains. Conclusions: Progress in treatment of dyspnea has not matched progress in elucidating underlying mechanisms. There is a critical need for interdisciplinary translational research to connect dyspnea mechanisms with clinical treatment and to validate dyspnea measures as patient-reported outcomes for clinical trials.
Nucleic Acids Research. Jan, 2012 | Pubmed ID: 22228831
XRCC4 and XLF are structurally related proteins important for DNA Ligase IV function. XRCC4 forms a tight complex with DNA Ligase IV while XLF interacts directly with XRCC4. Both XRCC4 and XLF form homodimers that can polymerize as heterotypic filaments independently of DNA Ligase IV. Emerging structural and in vitro biochemical data suggest that XRCC4 and XLF together generate a filamentous structure that promotes bridging between DNA molecules. Here, we show that ablating XRCC4's affinity for XLF results in DNA repair deficits including a surprising deficit in VDJ coding, but not signal end joining. These data are consistent with a model whereby XRCC4/XLF complexes hold DNA ends together-stringently required for coding end joining, but dispensable for signal end joining. Finally, DNA-PK phosphorylation of XRCC4/XLF complexes disrupt DNA bridging in vitro, suggesting a regulatory role for DNA-PK's phosphorylation of XRCC4/XLF complexes.
Toxicological Sciences : an Official Journal of the Society of Toxicology. Jan, 2012 | Pubmed ID: 22247004
Four non-volatile nerve agent surrogates, 4-nitrophenyl ethyl dimethylphosphoramidate (NEDPA, a tabun surrogate), 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate), and two sarin surrogates phthalimidyl isopropyl methylphosphonate (PIMP) and 4-nitrophenyl isopropyl methylphosphonate (NIMP), were synthesized and tested as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. These surrogates were designed to phosphorylate cholinesterases with the same moiety as their respective nerve agents, making them highly relevant for the study of cholinesterase reactivators. Surrogates were characterized by LC-MS and NMR. NEMP, PIMP and NIMP were potent inhibitors of rat brain, skeletal muscle, diaphragm and serum AChE, as well as human erythrocyte AChE and serum BuChE in vitro. PIMP was determined to degrade quickly in aqueous solution, making it useful for in vitro assays only, and NEDPA was not a potent inhibitor of AChE or BuChE in vitro; therefore, these two surrogates were not tested in subsequent in vivo studies. Sub-lethal dosages (yielding about 80% brain AChE inhibition) were determined for both the stable sarin surrogate, NIMP (0.325 mg/kg ip), and the VX surrogate, NEMP (0.4 mg/kg ip) in adult male rats. Time course studies indicated the time to peak brain AChE inhibition for both NIMP and NEMP to be one hour post exposure. Both surrogates yielded severe cholinergic signs. These dosages did not require the addition of atropine to prevent lethality and the rate of AChE aging was slow making these surrogates useful for reactivation studies both in vitro and in vivo. The surrogates synthesized in this study are potent yet safer to test than nerve agents, and are useful tools for initial screening of nerve agent oxime therapeutics.
A Novel Technique for Femoral Canal Occlusion During Cement Pressurization in Proximal Femoral Arthroplasty
The Journal of Arthroplasty. Jan, 2012 | Pubmed ID: 22152980
We describe a novel technique for occluding the femoral canal distal to the isthmus during proximal femoral arthroplasty. Synthetic bone models were reamed and sectioned to simulate loss of the proximal femur. Two experimental conditions were used. The first used no restrictor to act as a control. The second used calcium sulphate pellets impacted in distal femoral canal. A 100 × 12 mm Limb Preservation System stem (DePuy, Leeds, UK) was used in all experiments. We recorded cement pressure, leakage of cement, and penetration of cement into the femoral condyles. The calcium sulphate pellets prevented cement leakage, enabled higher cementing pressures, and prevented penetration of the cement into the femoral condyles. We would recommend this technique in cases where loss of proximal femoral bone loss requires the use of a cemented proximal femoral replacement.
Ethambutol Pharmacokinetic Variability is Linked to Body Mass in Overweight, Obese, and Extremely Obese People
Antimicrobial Agents and Chemotherapy. Mar, 2012 | Pubmed ID: 22155817
We conducted a prospective study of 18 adult volunteers (male-to-female ratio of 1) whose body mass index fell into categories of <25, 25 to 40, or >40 kg/m(2), who received a single oral dose of 1,600 mg ethambutol. Only individuals with normal renal function were recruited. The minimum body mass (M) was 45.6 kg, the median was 90.8 kg, and the maximum weight was 160.4 kg. Ethambutol pharmacokinetics were best described by a two-compartment model. Inclusion of weight as a covariate dramatically improved the model, with a relative likelihood approaching infinity. The typical clearance was 42.6 liters/h. Ethambutol systemic clearance was proportional to (M/45.6)(3/4) and thus obeyed fractal geometry-based laws. This means that the area under the concentration-time curve (AUC) actually decreased for obese patients compared to that for leaner patients, reducing chances of concentration-dependent toxicity. On the other hand, such reduced AUCs could lead to therapy failure. Thus, new and individualized ethambutol dosing regimens need to be designed for obese and extremely obese patients.
Association Between Use of Statins and Mortality Among Patients Hospitalized with Laboratory-confirmed Influenza Virus Infections: a Multistate Study
The Journal of Infectious Diseases. Jan, 2012 | Pubmed ID: 22170954
Statins may have anti-inflammatory and immunomodulatory effects that could reduce the risk of mortality from influenza virus infections.
Professional Case Management. Jan-Feb, 2012 | Pubmed ID: 22146637
The move to the Accountable Care Organization model of care calls for broad-sweeping structural, operational, and cultural changes in our health care systems. The use of predictive modeling as part of the discharge process is used as a way to highlight just one of the common processes that will need to be transformed to maximize reimbursement under the Accountable Care Organization model. The purpose of this article is to summarize what has been learned about predictive modeling from the population health management industry perspective, to discuss how that knowledge might be applied to discharge planning in the Accountable Care Organization model of patient care, and then to outline how the Accountable Care Organization environment presents various challenges, opportunities, and implications for the case management role.
Archives of Disease in Childhood. Education and Practice Edition. Feb, 2012 | Pubmed ID: 22036713
Movement Disorders : Official Journal of the Movement Disorder Society. Jan, 2012 | Pubmed ID: 21953509
Fatigue is one of the most disabling non-motor symptoms for people with Parkinson's disease. Exercise may modify fatigue. This study examines prescribed exercise effects on physical activity levels, well-being, and fatigue in Parkinson's disease.