bluuebunny/crossref_metadata_2025 huggingface dataset:
A theoretical and spectroscopic study of γ-crystalline and amorphous indometacin
Authors: Strachan Clare J , Rades Thomas , Gordon Keith C
Published: January 2007

Amorphous materials are prevalent in the pharmaceutical setting. Whether they are a help or hindrance, their physicochemical characteristics must be investigated. However, the amorphous form remains a challenge to characterise with many of its properties poorly understood. In this study, γ-crystalline and amorphous indometacin are investigated using vibrational spectroscopy and quantum chemical calculations. The structure of the single indometacin molecule and the dimer in the γ-form were optimised using density functional theory calculations. The optimised structures were similar to the conformations in the crystal form, suggesting that conformation of the molecules in the crystal may be close to the average molecular structure in less-ordered states. Infrared and Raman spectra were calculated from the optimised structures. Many modes in the calculated spectra could be matched with the experimental spectra of the γ-crystalline and amorphous forms, and a description of the matched modes has been provided. By analysis of the theoretical vibrational modes it was confirmed that the amorphous form of indometacin produced by quench cooling the melt consists predominantly of dimers, similar in structure to in the γ-crystalline form. In addition, differences in intermolecular bonding between the two forms were identified. Quantum mechanical calculations allow improved understanding of amorphous materials and their vibrational spectra.
The use of quantum chemistry in pharmaceutical research as illustrated by case studies of indometacin and carbamazepine
Authors: Gordon Keith C , McGoverin Cushla M , Strachan Clare J , Rades Thomas
Published: January 2007

A number of case studies that illustrate how quantum chemistry may be used in studying pharmaceutical systems are reviewed. A brief introduction to quantum methods is provided and the use of these methods in understanding the structure and properties of indometacin and carbamazepine is discussed. The use of calculated structures and molecular electrostatic potentials in developing quantitative structure-activity relationships is discussed along with the use of computation chemistry to predict spectroscopic properties.
2-Ethylhexyl-2,4,5-trimethoxycinnamate and di-(2-ethylhexyl)-2,4,5-trimethoxybenzalmalonate as novel UVA filters
Authors: Monhaphol Thitinun , Albinsson Bo , Wanichwecharungruang Supason Pattanaargson
Published: January 2007

A series of 2-ethylhexylmethoxy substituted cinnamates and benzalmalonates have been synthesized and characterized. 2-Ethylhexyl-2,4,5-trimethoxycinnamate (E8) and di-(2-ethylhexyl)-2,4,5-trimethoxybenzalmalonate (B8) show UVA absorption with high molar absorption coefficients (12000-14000 cm−1 M−1 at 350 nm). E8 undergoes trans to cis photoisomerization under UVA exposure causing the decrease in UV absorption efficiency. E8 is more photostable than butyl methoxydibenzoylmethane (BMDBM). For example, 41.64 J cm−2 UVA irradiation produces 20 ± 2% and 25 ± 2% loss in UV absorption for E8 and BMDBM, respectively. Similar irradiation produces no change in the UV absorption of B8. Both the oily liquid E8 and the yellow solid B8 can be dissolved in various organic solvents, ranging from methanol to hexane, various silicone fluids and 2-ethylhexyl-4-trimethoxycinnamate (EHMC, a widely used UVB filter). A liquid broadband filter comprising B8 and EHMC shows excellent photostability in both UVB and UVA regions.
Gastroprotective and cytotoxic effect of semisynthetic ferruginol derivatives
Authors: Areche Carlos , Rodríguez Jaime A , Razmilic Iván , Yáñez Tania , Theoduloz Cristina , Schmeda-Hirschmann Guillermo
Published: January 2007

The gastroprotective abietane diterpene ferruginol has been shown to present high cytotoxicity. In order to obtain active compounds with less cytotoxicity, 18 semisynthetic ferruginol derivatives and totarol were assessed for their gastroprotective effects in the HCl/ethanol-induced gastric lesion model in mice, as well as for cytotoxicity in human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). At 20 mg kg−1, the greatest gastroprotective effects were provided by abieta-8,11,13-triene (1), abieta-8,11,13-trien-12-yl-2-chloropropanoate (8), abieta-8,11,13-trien-12-yl propenoate (9), 12-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-abieta-8,11,13-triene (17) and 12-(β-D-galactopyranosyloxy)-abieta-8,11,13-triene (18), all of which were as active as the reference drug lansoprazole at 20 mg kg−1, reducing gastric lesions by 69, 76, 67, 72 and 61%, respectively. No relation was observed between lipophilicity and the gastroprotective effect. Compounds that showed the greatest cytotoxicity towards AGS cells were ferruginol (2), the corresponding formate (5), acetate (6), propionate (7), 8, 9, 12-(β-D-glucopyranosyloxy)-abieta-8,11,13-triene (16), 18 and totarol (20) (IC50 18–44 μM). Ferruginol and compounds 5–9, 16, 18 and 20 were the most toxic compounds against fibroblasts (IC50 19–56 μM), with a correlation to AGS cells. The derivative 19 was much more active against AGS cells than towards fibroblasts. The best activity/cytotoxicity ratio was found for compound 17, with a lesion index comparable with lansoprazole at 20 mg kg−1 and cytotoxicity >1000 μM towards MRC-5 and AGS cells, respectively. In conclusion, some derivatives showed a better gastroprotective effect/cytotoxicity ratio than the parent compound ferruginol. A total of 13 new compounds are reported here for the first time.
Ameliorating effects of essential oil from Acori graminei rhizoma on learning and memory in aged rats and mice
Authors: Zhang Hong , Han Ting , Yu Cheng-Hao , Rahman Khalid , Qin Lu-Ping , Peng Cheng
Published: January 2007

Although there are normal cognitive changes that take place as a person becomes older, ageing in humans is generally associated with a deterioration of cognitive performance, in particular of learning and memory. There are a number of herbal medicines that are reported to improve brain function and intelligence. In the present study, the ameliorating effects of an essential oil extracted from Acori graminei rhizoma on learning and memory in aged, dysmnesia rats and mice were determined using the step-down passive avoidance test and Y maze. Oral administration of the essential oil (0.02, 0.04 and 0.08 g kg−1) to rats for 30 days and to mice for 15 days improved the latency and number of errors in aged, dysmnesia rats and mice. The cerebral neurotransmitters in aged rats given the essential oil (0.02, 0.04, 0.08 g kg−1) for 30 days were also investigated, and increased levels of norepinephrine, dopamine and serotonin, and decreased levels of acetylcholinesterase activity were found. The results suggest that the essential oil improves cognitive function in aged animals possibly by increasing norepinephrine, dopamine and serotonin relative levels, and by decreasing the activity of acetylcholinesterase in the cerebra.
Biocompatibility of polypyrrole particles: an in-vivo study in mice
Authors: Ramanaviciene Almira , Kausaite Asta , Tautkus Stasys , Ramanavicius Arunas
Published: January 2007

The objectives of this study were the chemical synthesis of polypyrrole particles, the investigation and estimation of the impact of polypyrrole particle concentration, and the evaluation of the effect of duration of treatment on immune-related haematological parameters and peritoneum cells in mice. The results showed that chemically prepared polypyrrole particles did not have any detectable cytotoxic effect on mouse peritoneum cells. Polypyrrole particles did not induce any allergic response, nor did they affect spleen, kidney or liver indexes. Moreover, no effect of polypyrrole particles on immune-related haematological parameters was observed. No inflammation was detected in the peritoneum of mice after a 6-week period of treatment with polypyrrole particles. In conclusion, chemically synthesized polypyrrole particles showed good biocompatibility in mice and are attractive candidates for biomedical applications in-vivo.
Measurement of serum testosterone in women; what should we do?
Authors: Kane John , Middle Jonathan , Cawood Marion
Published: January 2007

All immunoassays for female serum testosterone give falsely high results in some samples. The effect is variable and cannot be predicted for any given sample. Inaccurate calibration or interference by cross-reacting substances is almost certainly the cause of the problem, but for many immunoassays, the exact nature of the interferent is not known. Some of the interference can be removed by employing an extraction step prior to immunoassay. The advent of fast simple and sensitive liquid chromatography tandem mass spectrometry methods offers an exciting alternative to immunoassay for serum testosterone measurement. It is recommended that all high serum testosterone concentrations in women are checked, before reporting, by a method which is accurate (i.e. minimal bias to isotope dilution gas chromatography mass spectrometry [ID-GCMS] method) and is not subject to interference. Action should also be taken by assay users, manufacturers, regulators and professional bodies to ensure accurate standardization and comparability of assays.
Simultaneous determination of androstenedione and testosterone in human serum by liquid chromatography-tandem mass spectrometry
Authors: Gallagher L M , Owen L J , Keevil B G
Published: January 2007

Background: We aimed to develop a sensitive assay to quantitate serum concentrations of both androstenedione and testosterone within the female range simultaneously, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for use in the routine clinical laboratory and to compare this method with immunoassay.

Method: Samples (200 μL) were prepared by liquid-liquid extraction using (1 mL) methyl-tert-butyl-ether. Deuterated androstenedione and testosterone were used as internal standards.

Results: The standard curve was linear to 50 nmol/L, the lower limit of quantitation was 0.25 nmol/L, and intra-and inter-assay coefficients of variation were < 10% for both androgens over the range 0.3-35 nmol/L. There was a poor relationship between the LC-MS/MS and the radioimmunoassay methods for androstenedione with the LC-MS/MS generally giving lower results. For testosterone, the LC-MS/MS and immunoassay methods compared well at all concentrations. However, when female samples only were examined, the agreement deteriorated.

Conclusions: We have developed a sensitive and precise LC-MS/MS method, which gives more accurate results for all androstenedione measurements and low testosterone concentrations than immunoassay.
Elevated serum dipeptidyl peptidase IV activity in patients with chronic tonsillitis
Authors: Vlahović P , Avramović V , Stanković M , Savić S , Todorović M
Published: January 2007

Background: Palatine tonsils represent the first place of contact for a variety of antigenic substances present in air and food. Upon antigen stimulation, the interactions between T and B lymphocytes in the tonsil are known to depend on the expression of different co-stimulatory molecules, including proteolytic ectoenzymes. Dipeptidyl peptidase IV (DPP IV) and aminopeptidase N (APN), as T lymphocyte co-stimulatory molecules, participate in the regulation of the immune response during inflammation.

Methods: In this study, the serum and lymphocyte enzymatic activity of DPP IV and APN was investigated in 32 patients, 13 with recurrent tonsillitis (RT) and 19 with tonsillar hypertrophy (TH), before and one month after tonsillectomy. The enzymatic activity of DPP IV and APN in tonsillar lymphocytes and serum was determined kinetically at 37°C using Gly-Pro- p-nitroanilide (for DPP IV) and Ala- p-nitroanilide (for APN) as chromogenic substrates.

Results: Significantly higher serum DPP IV and APN activities ( P<0.001) were found in TH patients compared with those with RT before tonsillectomy. DPP IV activity in TH patients was also elevated compared with the control of the same age ( P<0.001), whereas the activity of APN was the same as the control group. The activity of both enzymes was the same as of controls after tonsillectomy. In addition, the results show that DPP IV and APN activities in serum decrease significantly with age. Tonsillar lymphocytes demonstrated a wide range of DPP IV and APN activities without significant differences between the investigated groups.

Conclusion: An increased serum DPP IV activity was observed in TH patients compared with both RT patients and controls before tonsillectomy. After tonsillectomy, all activities were similar. The results suggest that serum DPP IV activity may have potential as a diagnostic marker for patients with TH.
Creatinine and glomerular filtration rate: evolution of an accommodation
Authors: Diskin Charles J
Published: January 2007

This brief review examines the history of the use of creatinine as a measure of renal function. While there are more accurate markers of glomerular filtration, creatinine was chosen for convenience. Since the relationship of creatinine to glomerular filtration depends upon a tenuous balance of counterbalancing factors, practitioners should be alert to situations that alter that balance. While the averaging of variations over time helps to avoid some of the problems with diurnal variations in the past, the present-day reliance upon equations based upon a solitary serum value is likely to amplify those problems in clinical situations when the effect of disease, medications, diet and time of day upon that balance are not considered.
The angiotensin II type 2 receptor gene polymorphism and body mass index in healthy Japanese women
Authors: Kotani Kazuhiko , Sakane Naoki , Saiga Kyoko , Tsuzaki Kokoro , Sano Yoshiko , Mu Haosheng , Kurozawa Youichi
Published: January 2007

Background: Angiotensin II (AngII), through the AngII type 2 receptor (AT2-R), might exert some effect on adipocyte-and lipogenesis-related biology. The Adenine/Cytosine 3123 (A/C3123) polymorphism in the AT2-R gene is reportedly involved in some diseases, such as hypertension.

Methods: A total of 201 healthy Japanese women (mean age 43.2 years) were enrolled in the study to investigate the association among the AT2-R A/C3123 polymorphism detected by polymerase chain reaction methods, body mass index (BMI) and other obesity-linked metabolic parameters (blood pressure, serum lipid/lipoprotein, plasma glucose).

Results: Homozygotes of the C-allele in the AT2-R A/C3123 polymorphism were associated with small but significant increases in BMI levels. There were no differences between genotype-based groups in the obesity-linked metabolic parameters.

Conclusion: These findings suggest that the AT2-R A/C3123 polymorphism could be a polymorphic marker related to BMI in Japanese women.
Effect of albumin concentration on serum cortisol measured by the Bayer Advia Centaur assay
Authors: Barnes S C , Swaminathan R
Published: January 2007

Introduction: A poor comparison was seen between the Bayer Advia Centaur and the Roche Elecsys cortisol methods using samples sent to the laboratory for cortisol analysis. They were predominantly from patients attending the Endocrine outpatients clinic or patients in the intensive therapy unit. We investigated the effect of albumin concentration on the performance of both assays.

Methods: For the samples used in the patient comparison, the laboratory database was searched for any concomitant albumin concentrations (Beckman LX20 BCP method). A series of recovery experiments were performed combining samples with normal albumin and undetectable cortisol concentrations with samples with detectable cortisol but low albumin concentrations.

Results: Albumin concentration accounts for almost 50% of the variation in the difference between the two methods. The Bayer Advia Centaur method shows significant under-recovery at albumin concentrations lower than 24 g/L.

Conclusion: This under-recovery will significantly affect the diagnosis of adrenal insufficiency in critically ill patients with low albumin concentrations.
Autoantibodies against tumour suppressor protein p53 in pleural effusions of patients with tuberculosis pleurisy
Authors: Wang L , Chang Y-H , Lee Y-L , Shih C-M , Hsu Y-T , Shen G-H , Haung M-L , Shiau M-Y
Published: January 2007

Background: Autoantibodies against the p53 proteins (p53 Abs) can be detected in the serum, ascites, saliva and pleural effusions of various malignant patients. It is suggested that p53 Abs in pleural effusions might have some value for tumour diagnosis, prognosis or monitoring. The present study investigated the prevalence of p53 Abs in the pleural effusions of 90 patients with various diseases.

Methods: Patients with suspicious pleural effusions in chest film received thoracocentasis and their pleural effusions were collected. The presence of p53 Abs in effusion was detected by immunoblotting. Differences of p53 Abs with respect to the patient's age, gender, white blood cell count, lactate dehydrogenase, total proteins and adenosine deaminase scores were calculated by -2-test.

Results: p53 Abs were detected in 14.4% (13/90) of our patients, with prevalences of 10.5% (6/57) and 21.2% (7/33) among patients with benign and malignant diseases, respectively. Notably, 16.1% (5/31) of patients with tuberculosis pleurisy were positive for p53 Abs. These five patients had no history of cancer and, so far, have had no manifestations related to tumorigenesis.

Conclusions: As far as we know, this is the first report regarding the detection of p53 Abs in pleural effusions from patients with tuberculosis pleurisy.
The influence of a cooked-meat meal on estimated glomerular filtration rate
Authors: Preiss David J , Godber Ian M , Lamb Edmund J , Dalton R Neil , Gunn Ian R
Published: January 2007

Background: Chronic kidney disease (CKD) is an important but under-recognized condition. Recent national guidelines have recommended that biochemistry laboratories report estimated GFR (eGFR) to improve diagnosis of CKD and facilitate disease staging and management. Previous reports have suggested that intake of large amounts of cooked meat can lead to a significant increase in serum creatinine concentration.

Methods: Participants ( n = 32), consisting of 17 healthy volunteers and 15 outpatients, were recruited. Measurement of serum creatinine (kinetic Jaffe method, enzymatic, isotope-dilution mass spectrometry [IDMS]) and cystatin C, and calculation of eGFR were carried out before (i) and after a meal containing cooked meat (ii) and a meat-free meal (iii).

Results: Following intake of cooked meat, median serum creatinine concentration (kinetic Jaffe) increased from 80.5 µmol/L preprandially to 101.0 µmol/L 1-2 h postprandially ( P<0.0001), and 99.0 µmol/L 3-4 h postprandially ( P<0.0001). Median eGFR decreased from 84.0 mL/min/1.73 m2 preprandially to 59.5 mL/min/1.73 m2 1-2 h postprandially ( P<0.0001), and 64.0 mL/min/1.73m2 3-4 h postprandially ( P<0.0001). Consumption of non-meat-containing meals had little impact on serum creatinine (kinetic Jaffe) and eGFR. Changes in serum creatinine were similar using all three methods, and cystatin C concentration was generally uninfluenced by food intake.

Conclusions: Intake of cooked meat has a significant effect on serum creatinine concentration and eGFR. Misclassification of CKD is possible if measurements are made after meals containing cooked meat. Clinicians should ensure that CKD classification is based on samples taken in the appropriate conditions: either fasting or after avoidance of cooked meat on the day of sampling. National guidelines which overlook this factor should be revisited.
Steatosis and hepatic markers before and shortly after bariatric surgery
Authors: de Abreu M R A , Ramos A P P , Vendramini R C , Brunetti I L , Pepato M T
Published: January 2007

Background We present new findings on liver steatosis detected in a group of 20 morbidly obese patients who were reassessed shortly after bariatric surgery (BS) by assaying hepatic markers in their serum.

Methods: We assayed aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, γ-glutamyl transferase ( γ-GT), cholinesterase, cholesterol, total protein, and albumin, and measured the weight and the body mass index (BMI) of patients, before and one and three months after surgery.

Results: There were significant reductions in BMI following surgery and also falls in transaminases and γ-GT activities three months after BS. No changes occurred in other parameters between periods, except that cholesterol was above reference values before BS and fell to normal levels three months after BS.

Conclusions: We suggest that before undergoing surgery, the patients suffered from slight steatosis, while after BS the reduction in AST and γ-GT indicated that this condition was corrected within three months. Moreover, these enzymes may be useful markers for excess fat in the liver.
Guidelines for the performance of the sweat test for the diagnosis of cystic fibrosis
Authors: Green Anne , Kirk Jean ,   The Guidelines Development Group
Published: January 2007

A multidisciplinary group (representing various professional bodies and supported by the Cystic Fibrosis Trust) has developed evidence-based guidelines for the performance of the sweat test in the UK. The guidelines cover patient information, subject suitability, sweat collection, sweat analysis, quality, interpretation of results, and responsibility for testing and training. The guidelines were produced following a detailed literature search by the process described by the Royal College of Paediatrics and Child Health (RCPCH), using the Scottish Intercollegiate Guidelines Network 1 (SIGN 1) criteria to grade the evidence. Recommendations are graded A, B, or C, depending on the level of evidence. The grade B recommendations (there were no grade A recommendations) were subsequently appraised and endorsed as part of the RCPCH process, according to Appraisal of Guidelines for Research and Evaluation in Europe (AGREE). The recommendations are summarized in tabular form representing the final version incorporating the comments from the appraisal process. Both the appraisal comments and the full evidence base can be found on www.rcpch.ac.uk/publications/clinical_docs.html. The full guidelines can also be found on http://www.ukneqas.org.uk/guidelines.htm.
Laboratory testing for C1 inhibitor deficiency: a comparison of two approaches to C1 inhibitor function
Authors: Gompels M M , Lock R J
Published: January 2007

Background: C1 inhibitor deficiency may be hereditary or acquired. It is characterized by absent or poorly functioning C1 inhibitor. The disorder is rare, with prevalence estimated at 1/50,000. The very low incidence of the condition makes the sensitivity and specificity of assays used particularly important. Two different methods are commercially available to measure C1 inhibitor function. There are few data comparing these assays.

Methods: Two assays of C1 inhibitor function (C1 inhibitor-C1s complex formation or inhibition of C1 esterase cleavage of artificial substrate [colorimetric]) were compared in 71 patients (28 hereditary angioedema, 2 acquired angioedema and 41 controls).

Results: Qualitatively, the two assays showed good correspondence (92%). Six of 71 results were discordant. Correlation in quantitative terms was moderate ( R = 0.81).

Conclusions: Both assays show high sensitivity for hereditary/acquired angioedema. The colorimetric assay is more prone to false-positive results. However, clinical interpretation is not adversely affected.
Evidence of cardiomyocyte necrosis in glycogen storage disease type II
Authors: Gaze David C , Lawson Graham J , Harris Adam , Collinson Paul O
Published: January 2007

Adult-onset glycogen storage disease type II (GSD-II), unlike the infantile form, is not normally associated with coexisting cardiovascular pathologies. In infantile onset GSD-II, cardiomyopathy is a common feature, and mutations in the genes for cardiac troponin T and I are likely to be involved. This case report describes a 39-year-old man with no classical risk factors for premature cardiac disease who presented with central chest pain and shortness of breath. Serum aspartate transaminase (AST) had been consistently elevated for 15 years. Adult GSD-II had been diagnosed two years previously by muscle biopsy. On presentation, there was an elevated serum creatine kinase and AST. Electrocardiography and echocardiography were both normal, and an acute coronary syndrome was ruled out. Cardiac Troponin T (cTnT) was found to be positive at 0.1 μg/L using a Cardiac Reader, subsequently confirmed on an Elecsys 1010 (both from Roche Diagnostics, Lewes, UK). cTnT may therefore be a useful biomarker in examining subclinical cardiac involvement in GSD-II patients.
Oxidative and nitrosative stress in acute ischaemic stroke
Authors: Şeneş Mehmet , Kazan Nuran , Coşkun Özlem , Zengi Oğuzhan , Inan Levent , Yücel Doğan
Published: January 2007

Background: Increased nitric oxide (NO) production may result in further brain damage via nitric oxide synthase uncoupling in patients with acute ischaemic stroke by increasing free radical formation and oxidative stress. In this connection, we measured nitrite and nitrate (NO metabolites), ischaemia-modified albumin (IMA) and thiobarbituric acid-reactive substances (TBARS) in patients with ischaemic stroke.

Methods: We studied 41 patients with ischaemic stroke (22 men and 19 women, aged 65-13 years) and 37 age- and sex-matched controls (22 men and 15 women, aged 65-8 years). Blood samples were drawn within the first 24 h from the onset of symptoms in the patient group. Fasting morning samples were used in the control group. Concentrations of nitrite and nitrate were determined by Griess reagent; concentrations of IMA were determined by the albumin cobalt-binding test; and concentrations of TBARS were determined colorimetrically by thiobarbituric acid.

Results: Nitrate, IMA and TBARS concentrations were significantly increased compared with controls ( P<0.005, P<0.001, and P=0.01, respectively).

Conclusions: Patients with acute ischaemic stroke exhibit abnormalities in a range of markers of increased nitrosative and oxidative stress. These abnormalities may contribute to greater brain damage in patients with acute ischaemic stress.
Silent growth hormone secreting pituitary adenomas: IGF-1 is not sufficient to exclude growth hormone excess
Authors: Kalavalapalli S , Reid H , Kane J , Buckler H , Trainer P , Heald A H
Published: January 2007

Circulating insulin-like growth factor-1 (IGF-1) is increasingly being used as a screening test and in ongoing monitoring of treated acromegaly. We here present three cases of women (two of whom were on the oestrogen containing contraceptive pill at the time of presentation) who had normal circulating IGF-1 and no overt clinical features of acromegaly at the time of their pituitary surgery. Postoperatively, all were confirmed to have growth hormone excess in keeping with the presence of active somatotroph pituitary adenomas. We suggest that for optimal patient management, formal evaluation of growth hormone status with oral glucose tolerance testing should ideally be performed on all individuals for whom pituitary surgery is planned.
The sweat test for the diagnosis of cystic fibrosis - a personal experience of guideline production
Authors: Green Anne
Published: January 2007

The need for evidence-based guidelines as to how to conduct the sweat test in the UK was highlighted in 2000 by the National External Quality Assessment Scheme Specialist Advisory Committee. A Guideline Group supported by several professional bodies was subsequently convened and formal evidence-based guidelines were produced and published in 2003. The process of undertaking guideline production is summarized here, together with the author's personal opinions about the experience and highlights of the shortcomings and lessons learnt from the project. In summary, production of evidence-based guidelines is a long process and is only worth the effort (both man hours and financial) if the recommendations are subsequently adopted into clinical practice and in turn improve patient care. The emphasis for the future should be to assess the impact and value of evidence-based guidelines and promote their introduction into local practice as part of care pathways. A growing number of guideline initiatives emphasizes the importance of and a need for an overarching coordinating structure to overcome problems of duplication and enable interested professionals from different disciplines to work on related initiatives.
Rurality, remoteness and the change process: evidence from a study of maternity services in the north of Scotland
Authors: Farmer Jane , Dawson Patrick , Martin Elizabeth , Tucker Janet
Published: January 2007

There is a wealth of material on 'how to do' change plus empirical work revealing change process complexity. In health care, the relevance of context is highlighted, but studies of rural health-care change have focused on community impacts. There is little to inform health-care managers of how remoteness and rurality impact upon change processes. This study considered Scottish maternity units and aimed to identify issues in the change process associated with rurality and remoteness. Six units were purposively selected and 131 interviews were conducted with managers, staff and community members over 15 months. Analysis induced themes pertinent to remoteness and rurality. These included: perceived 'distance' between senior managers imposing change and the wider community of staff and residents; perceptions of community vulnerability; and tensions arising from working in small teams and living in small communities. The study provides useful insights for rural managers at a time of considerable service reconfiguration.
Improving the recruitment and return of nurses and allied health professionals: a quantitative study
Authors: Coombs Crispin R , Arnold John , Loan-Clarke John , Wilkinson Adrian , Park Jenny , Preston Diane
Published: January 2007

The United Kingdom National Health Service (NHS) is continuing to experience recruitment and retention problems of nursing and allied health profession staff. Consequently, the need to study and understand the key factors that encourage or dissuade people to work for the NHS remains a major research and policy issue. This study provides well-focused, independent research to explore how the NHS can be made more attractive for potential new recruits and possible returners. The views of potential recruits and returners interested in working for the NHS as either a qualified nurse, physiotherapist or radiographer were explored through a postal questionnaire survey which achieved a response rate of 23%. Analysis of the results indicate that the strongest predictor of intention to work for the NHS in one of the three professions was the attitude held by respondents. These attitudes in turn were most influenced by the extent to which people perceived that NHS work as a qualified nurse, physiotherapist or radiographer offered positive features, i.e. rewarding career, teamwork and a chance to help people and to get to know them. The views of family and friends regarding working for the NHS were also important as was the belief in one's ability to secure an NHS job.
Managing and analysing a large health-care system database for predicting in-hospital mortality among acute myocardial infarction patients
Authors: Bae Sejong , Zhang Huiling , Rivers Patrick A , Singh Karan P
Published: January 2007

There is increasing interest in the identification of predictors of risk for in-hospital mortality due to acute myocardial infarction (AMI). This study identified significant predictors of in-hospital mortality among AMI patients using a patient level clinical database.

The study population consisted of 4167 cases admitted between October 1999 and April 2001 with a principal diagnosis of AMI to 36 hospitals in three US states. Of the 182 available variables in the clinical data set, 30 variables were used as candidate predictors, and 19 showed significant univariate association with AMI in-hospital mortality. By applying multiple logistic regression and stepwise selection, a final prediction model for AMI in-hospital mortality was developed. Variables included in the final model were age, arrived from cardiac rehabilitation centre, cardiopulmonary resuscitation (CPR) on arrival, Killip class, AMI with co-morbid conditions, AMI with complications, percutaneous transluminal coronary angioplasty (PTCA) performed, β-blockers given, angiotensin-converting enzyme (ACE) inhibitors given, Plavix given.

A 10-variable in-hospital mortality prediction model for AMI patients, which includes both risk factors and beneficial treatment procedures, was developed. x2 goodness of fit test suggested a good fit for the model.
Proposed further tort reform after the NHS Redress Act: a Trojan Horse from Making Amends
Authors: Gooderham Peter
Published: January 2007

Recommendation 17 of Making Amends proposes reform or repeal of section 2(4) of the Law Reform (Personal Injuries) Act. Reform or repeal of section 2(4) may be superficially attractive based on the potential problem of double recovery. There are, however, legal limits to double recovery actually happening and reliable estimates of the extent of the problem seem not to be available. Repeal may have limited financial savings for the National Health Service (NHS) but may have significant benefits for those who indemnify other potential Defendants. Recommendation 17 threatens to remove the option to remain at home for severely-injured victims of clinical negligence in the NHS. As such, this undermines the basis of tort compensation.
Peer review
Authors: Cheadle Patrick
Published: January 2007

An explanation of the principles of peer review, charting the development of peer review to date and providing a guide to practitioners in preparing for the new ways of working with the Legal Services Commission focussing on clinical negligence.
Medicolegal aspects of glaucoma
Authors: Ali MN , Fraser SG
Published: January 2007

This article analyses medicolegal aspects of glaucoma, employing data from the NHS Litigation Authority (UK) and the Physician Insurers Association of America (USA). The most common form of glaucoma is a chronic, progressive condition which usually entails life-long follow-up, the longitudinal profile presenting many sequential opportunities for error. However, this analysis shows that glaucoma claims are uncommon (43 claims in 10 years in the UK), but when they do occur they are more likely to lead to payment of damages, and the levels of damages paid tend to be higher than for the rest of ophthalmology. Failure or delay in diagnosing, treating and monitoring glaucoma account for approximately one-half of claims in the UK. Surgery-related claims are rare.
Clinical risk management: paediatric ophthalmology and strabismus
Authors: Adams GGW , Sloper John
Published: January 2007

Paediatric ophthalmology covers all eye problems in children up to the age of 16 years. Strabismus can occur at any age. This article discusses issues within these specialties that could or have resulted in litigation. The issues discussed are cerebral visual impairment, retinopathy of prematurity, postnatal and 6 week examination, non-accidental injury, papilloedema, squint, amblyopia, functional blindness, shunt blockage, sinus surgery and orbital blow out fracture.
Risk management in cataract surgery
Authors: Ionides Alexander
Published: January 2007

This article discusses medicolegal and patient safety issues relating to the most commonly performed surgical operation in the UK. Patient safety incidents in cataract surgery are discussed and preventive measures at organizational and individual levels are outlined. Claims relating to cataract surgery account for one-third of settled claims in ophthalmology. The nature of cataract surgery claims is reviewed and ways to avoid ending up in court are recommended.
Risk management, adverse events and litigation in vitreoretinal surgery
Authors: Fetherston Tim
Published: January 2007

Using data from the UK National Reporting and Learning System and the National Health Service Litigation Authority, this paper assesses trends in patient safety incidents and litigation in relation to ophthalmic surgery generally and vitreoretinal (VR) surgery in particular. Examples of human error and equipment-related incidents in VR surgery are discussed. Data from incident reporting and litigation should be interpreted with care as these are influenced by many factors. An open culture, improved reporting and prioritisation of patient safety will help provide further insight into the prevalence and causes of patient safety incidents in VR surgery.
Case: Sympathetic ophthalmia following elective surgery
Authors: Whittaker Rogers v
Published: January 2007

In determining the adequacy of information provided by doctors to their patients, the English courts adopt the Bolam test - the standard of care of a responsible body of medical opinion - but following the decision in Rogers v Whittaker [1992] 175 CLR 479 Australian courts apply a different test - material risk to which a patient is likely to attach significance. This article provides a summary of the proceedings and judgment in this case, and discusses its contemporary significance.
Safer practice in ophthalmology
Authors: Fraser Scott
Published: January 2007

Ophthalmology is thought to be a relatively safe specialty, but the articles in this Clinical Focus question the validity of this perception. The chance of harm may be relatively small but the potential consequences are severe. Fatal error is uncommon but loss of sight is a great disability - and fertile soil for litigation.
Interaction of yeast RNA-binding proteins Nrd1 and Nab3 with RNA polymerase II terminator elements
Authors: Carroll Kristina L. , Ghirlando Rodolfo , Ames Jessica M. , Corden Jeffry L.
Published: January 2007

Yeast RNA-binding proteins Nrd1 and Nab3 direct transcription termination of sn/snoRNA transcripts, some mRNA transcripts, and a class of intergenic and anti-sense transcripts. Recognition of Nrd1- and Nab3-binding sites is a critical first step in the termination and subsequent processing or degradation of these transcripts. In this article, we describe the purification and characterization of an Nrd1–Nab3 heterodimer. This Nrd1–Nab3 complex binds specifically to RNA sequences derived from a snoRNA terminator. The relative binding to mutant terminators correlates with the in vivo termination efficiency of these mutations, indicating that the primary specificity determinant in nonpoly(A) termination is Nrd1–Nab3 binding. In addition, several snoRNA terminators contain multiple Nrd1- and Nab3-binding sites and we show that multiple heterodimers bind cooperatively to one of these terminators in vitro.
Large-scale production of dsRNA and siRNA pools for RNA interference utilizing bacteriophage ϕ6 RNA-dependent RNA polymerase
Authors: Aalto Antti P. , Sarin L. Peter , van Dijk Alberdina A. , Saarma Mart , Poranen Minna M. , Arumäe Urmas , Bamford Dennis H.
Published: January 2007

The discovery of RNA interference (RNAi) has revolutionized biological research and has a huge potential for therapy. Since small double-stranded RNAs (dsRNAs) are required for various RNAi applications, there is a need for cost-effective methods for producing large quantities of high-quality dsRNA. We present two novel, flexible virus-based systems for the efficient production of dsRNA: (1) an in vitro system utilizing the combination of T7 RNA polymerase and RNA-dependent RNA polymerase (RdRP) of bacteriophage ϕ6 to generate dsRNA molecules of practically unlimited length, and (2) an in vivo RNA replication system based on carrier state bacterial cells containing the ϕ6 polymerase complex to produce virtually unlimited amounts of dsRNA of up to 4.0 kb. We show that pools of small interfering RNAs (siRNAs) derived from dsRNA produced by these systems significantly decreased the expression of a transgene (eGFP) in HeLa cells and blocked endogenous pro-apoptotic BAX expression and subsequent cell death in cultured sympathetic neurons.
The imprinted H19 noncoding RNA is a primary microRNA precursor
Authors: Cai Xuezhong , Cullen Bryan R.
Published: January 2007

Although H19 was the first imprinted noncoding transcript to be identified, the function of this conserved RNA has remained unclear. Here, we identify a 23-nucleotide microRNA derived from H19 that is endogenously expressed in human keratinocytes and neonatal mice and overexpressed in cells transfected with human or mouse H19 expression plasmids. These data demonstrate that H19 can function as a primary microRNA precursor and suggest that H19 expression results in the post-transcriptional downregulation of specific mRNAs during vertebrate development.
Comparison of siRNA-induced off-target RNA and protein effects
Authors: Alemán Lourdes M. , Doench John , Sharp Phillip A.
Published: January 2007

The downregulation of many mRNAs has been observed through bioinformatic analysis of microarray results following transfection of short interfering RNAs (siRNAs). Many of these mRNA changes are due to the interaction of the siRNA guide strand with partially complementary sites and thus are considered “off-target” effects. To examine the mRNA:siRNA interactions important for off-target effects, we generated a panel of mRNA:siRNA combinations containing single and double mismatches, bulges, and noncanonical base-pairing interactions in the 9th, 10th, and 11th positions of two siRNA binding sites located in the 3′ UTR of an integrated reporter gene. Approximately half of the mRNA:siRNA combinations containing mismatches in positions 9–11 result in a twofold or more mRNA decrease with varying degrees of protein knockdown. However, mRNA and protein analysis of the various mRNA:siRNA combinations reveals instances in which mRNA and protein levels do not correlate. Analysis of the resulting degradation products recovered from an imperfectly complementary siRNA interaction with an endogenous gene reveals a small fraction of products that map to the canonical siRNA cleavage site. Furthermore, downregulation of ARGONAUTE 2 (AGO2), the only AGO family protein known to catalyze canonical siRNA-mediated cleavage, did not significantly affect the degree of mRNA knockdown observed for one of the stably expressed reporters after transfection of an imperfectly complementary siRNA. These results indicate that although some degree of canonical siRNA cleavage can take place between a siRNA and an off-target transcript, most off-target mRNA reductions are likely attributable to AGO2-independent degradation processes.
The eIF4G–homolog p97 can activate translation independent of caspase cleavage
Authors: Nousch Marco , Reed Victoria , Bryson-Richardson Robert J. , Currie Peter D. , Preiss Thomas
Published: January 2007

The eukaryotic initiation factor (eIF) 4G family plays a central role during translation initiation, bridging between the 5′ and 3′ ends of the mRNA via its N-terminal third while recruiting other factors and ribosomes through its central and C-terminal third. The protein p97/NAT1/DAP5 is homologous to the central and C-terminal thirds of eIF4G. p97 has long been considered to be a translational repressor under normal cellular conditions. Further, caspase cleavage liberates a p86 fragment that is thought to mediate cap-independent translation in apoptotic cells. We report here that, surprisingly, human p97 is polysome associated in proliferating cells and moves to stress granules in stressed, nonapoptotic cells. Tethered-function studies in living cells show that human p97 and p86 both can activate translation; however, we were unable to detect polysome association of p86 in apoptotic cells. We further characterized the zebrafish orthologs of p97, and found both to be expressed throughout embryonic development. Their simultaneous knockdown by morpholino injection led to impaired mesoderm formation and early embryonic lethality, indicating conservation of embryonic p97 function from fish to mammals. These data indicate that full-length p97 is a translational activator with essential role(s) in unstressed cells, suggesting a reassessment of current models of p97 function.
Isolation of polysome-bound mRNA from solid tissues amenable for RT-PCR and profiling experiments
Authors: Del Prete M. Julieta , Vernal Rolando , Dolznig Helmut , Müllner Ernst W. , Garcia-Sanz Jose A.
Published: January 2007

Using cell lines and primary cells, it has been shown that translation control plays a key role regulating gene expression during physiological and pathological conditions. The relevance of this type of regulation in vivo (tissues, organs) remains to be elucidated, due to the lack of an efficient method for polysome-bound fractionation of solid tissue RNA samples. A simple and efficient method is described, in which tissue samples were pulverized in liquid nitrogen and lysed with NP40-lysis buffer in the presence of the RNAse inhibitors RNAsin and vanadyl-ribonucleoside complex. After cell lysis, the cytoplasmic extract was loaded into sucrose gradients, fractionated, and RNA prepared from each fraction. The obtained RNA was reverse transcribed with a low efficiency, a problem that was overcome by purifying polyA+ RNA. Aiming to use small quantities of solid tissue samples (10–20 mg/sample), polyA+ RNA purification was discarded, and the different components were individually screened for a negative effect on reverse transcription. The polysaccharide heparin, which is present as a nonspecific RNAse inhibitor, inhibits reverse transcriptase activity, and must be removed from RNA samples for an efficient reaction. Heparin was successfully removed by precipitation of the RNA with lithium chloride, as demonstrated by the reversal of the inhibition on RT-PCR reactions. In summary, we present a reliable method allowing us to prepare high-quality polysome-bound mRNA from small quantities of liquid-nitrogen–frozen solid tissue samples from both human and mouse origin, amenable for Northern blotting, RT-PCR reactions, and expression profiling analyses.
The Spanish Minerva: Imagining Teresa of Avila as Patron Saint in Seventeenth-Century Spain
Authors: Rowe Erin Kathleen
Published: January 2007

In the early seventeenth-century, a movement began to elevate Teresa of Avila to co-patron saint of Spain (alongside the traditional patron, Santiago); this movement changed the ways in which the saint was imagined in both visual images and metaphors. Through a close reading of treatises and sermons, this article examines how Teresa's elevation to national patron saint required a distinctive symbolism that reflected national, rather than ecclesiastical, concerns. She was therefore transformed from author and founder into the "Spanish Minerva." By exploring this transformation, the article investigates the continual process of construction that saints' cults underwent and the roles played by conflict and gender in this process.
C.T. Gillin, D. MacGregor, and T.R. Klassen (Eds.). Time's Up! Mandatory Retirement in Canada. Toronto: James Lorimer, 2005.
Authors: Béland Daniel
Published: January 2007

Cet ouvrage collectif propose une analyse du débat canadien sur l'abolition de la retraite obligatoire. À l'exception d'un chapitre, le livre propose une critique en règle de cette pratique, avec un accent sur le monde universitaire. Facile à lire et souvent intéressant, ce livre souffre de deux lacunes majeures. Premièrement, les discussions historiques et comparatives sont éparpillées dans plusieurs chapitres différents, ce qui complique la compréhension des grands enjeux du débat sur la retraite obligatoire. Deuxièmement, ce livre n'explique pas vraiment pourquoi deux des dix provinces canadiennes (le Québec et le Manitoba) ont aboli la retraite obligatoire alors que les huit autres n'ont fait qu'en restreindre l'application. Malgré ces deux lacunes, cet ouvrage collectif représente une contribution inégale mais significative au débat contemporain sur l'avenir de la retraite obligatoire au Canada.