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Internal initiation in Saccharomyces cerevisiae mediated by an initiator tRNA/eIF2-independent internal ribosome entry site element.

Internal initiation of translation can be mediated by specific internal ribosome entry site (IRES) elements that are located in certain mammalian and viral mRNA molecules. Thus far, these mammalian cellular and viral IRES elements have not been shown to function in the yeast Saccharomyces cerevisiae. We report here that a recently discovered IRES located in the genome of cricket paralysis virus can direct the efficient translation of a second URA3 cistron in dicistronic mRNAs in S. cerevisiae, thereby conferring uracil-independent growth. Curiously, the IRES functions poorly in wild-type yeast but functions efficiently either in the presence of constitutive expression of the eIF2 kinase GCN2 or in cells that have two initiator tRNA(met) genes disrupted. Both of these conditions have been shown to lower the amounts of ternary eIF2-GTP/initiator tRNA(met) complexes. Furthermore, tRNA(met)-independent initiation was also observed in translation-competent extracts prepared from S. cerevisiae in the presence of edeine, a compound that has been shown to interfere with start codon recognition by ribosomal subunits carrying ternary complexes. Therefore, the cricket paralysis virus IRES is likely to recruit ribosomes by internal initiation in S. cerevisiae in the absence of eIF2 and initiator tRNA(met), by the same mechanism of factor-independent ribosome recruitment used in mammalian cells. These findings will allow the use of yeast genetics to determine the mechanism of internal ribosome entry.

Base Sequence↗

Working and training as an intern: a national survey of Irish interns.

The Medical Council of Ireland recently introduced some initiatives to enhance the education and training of interns. These include the development of a generic job description, a logbook to monitor training outcomes and a national network of supervisors to plan and oversee intern training. To get feedback on the impact of these reforms, the Medical Council surveyed all interns with Irish addresses in March 2003. Three hundred (65%) of 461 interns responded. The majority provided positive feedback on many aspects of their education and training, their work environment and professional relationships. However, a majority also reported a lack of protected time for education, a lack of formal educational programmes, insufficient feedback on performance and an unnecessarily stressful work environment. Overall, 61% reported being bullied and 4% had experienced sexual harassment. While feedback on the Irish internship experience is generally positive, further work is necessary to address the problems identified.

Agonistic Behavior↗

The multicentre trial philosophy in stress echocardiography: lessons learned from the EPIC study. EPIC-EDIC Study Project. Echo Persantine International Cooperative Study. Echo-Dobutamine International Cooperative Study.

The scientific assessment of diagnostic tests should not be based upon a small series of results published by the best academic institutions, but ought to require large scale, multicentre validation founded on grass roots institutions with real doctors, real patients and real problems. To this purpose, an international network of stress echo laboratories has been organized, and within a few years has collected data from thousands of studies using pharmacological stress echocardiography, performed with either dipyridamole (EPIC: Echo Persantine International Cooperative Study) or dobutamine (EDIC: Echo Dobutamine International Cooperative Study) stresses. In a widely deregulated field, all network laboratories have agreed: to pass a quality control examination on stress echo reading before entering the study; to adopt an identical drug infusion protocol; to code similarly the LV segments; and to adopt a common scoring system for wall motion analysis. A minimum amount of historical, clinical, and-when available-stress electrocardiographic, angiographic and follow-up data have been collected on each patient, and disseminated in the various centres, facilitating the creation of an international stress echo language that will help, not only the production of high quality scientific data, but also the build up of a common stress echo lab, with a standardized way of making the studies, unifying the methods and terminology, and archiving data. To date, we have 50 echo laboratories from 15 nations across four continents (Europe, America, Asia and Africa) actively involved in this project. These data will ultimately fill the gap between the academic theory of journals and the pragmatic experience of daily life in a busy echocardiographic laboratory.

Echocardiography↗

Internal anal sphincter function following lateral internal sphincterotomy for anal fissure: a long-term manometric study.

BACKGROUND: Anal fissure is a common and painful disorder. Its relation to hypertonic anal sphincter is controversial. The most common surgical treatment of chronic anal fissure is lateral internal sphincterotomy. OBJECTIVE: The aim of this study was to evaluate long-term manometric results of sphincter healing following lateral internal sphincterotomy. PATIENTS AND METHODS: Between 2000 and 2003, 50 patients with anal fissure were included in this study and underwent sphincterotomy; 12 healthy patients served as controls. All patients with anal fissure underwent manometric evaluation using a 6-channel perfusion catheter. All patients were examined 1 month before surgery and 1, 3, 6, and 12 months following surgery. The control group had 3 manometric evaluations 6 months apart. RESULTS: The mean basal resting pressure before surgery was 138 +/- 28 mm Hg. One month after surgery, the pressure dropped to 86 +/- 15 mm Hg (P < 0.0001) and gradually rose to a plateau at 12 months (110 +/- 18 mm Hg, P < 0.0001). At 12 months, the manometric pressure was significantly lower than the baseline (P < 0.0001). However, manometric measurements in the fissure group were still significantly higher than in the control group (110 +/- 18 versus 73 +/- 4.8 mm Hg, P < 0.0001). All patients were free of symptoms at the 12-month follow-up. CONCLUSION: Lateral internal sphincterotomy caused a significant decline in the resting anal pressure. During the first year following surgery, the tone of the internal anal sphincter gradually increased, indicating recovery, but still remained significantly lower than before surgery. However, postoperative resting pressures were higher than those in the control, and no patient suffered any permanent problems with incontinence, so this decrease may not be clinically significant.

Adult↗

Studies on phage internal proteins: formation of internal protein - T2 DNA complexes in vivo.

Internal proteins, synthesized in T2-infected Escherichia coli B cells were recovered from bacterial membranes during the early stages of infection. Approx. 15 min after the onset of infection, T2 and T4 internal proteins were released from the bacterial membranes and sedimented along with newly synthesized phage DNA. Internal protein-DNA complexes were also obtained by chromatography on hydroxylapatite columns. Internal proteins were not released from bacterial membranes after infection with amber mutants defective in genes 21, 22 and 23. It has been suggested that these complexes are intermediates in T-even phage morphogenesis.

Cell Membrane↗

A comparison of early mortality and morbidity after single and bilateral internal mammary artery grafting with the free right internal mammary artery.

OBJECTIVE: To compare differences in early mortality and morbidity in patients receiving a single internal mammary artery graft (SIMA) with those receiving bilateral internal mammary artery grafts (BIMA) with a free right internal mammary artery (RIMA). DESIGN: Retrospective analysis of 150 patients undergoing BIMA grafting between 1989-1992 who were carefully matched with 150 patients undergoing SIMA grafting between 1987-1992 for known cardiovascular risk factors, extent of coronary disease, left ventricular function, and number of coronary grafts. Operative variables noted included aortic cross clamp time and bypass time. Postoperative cardiac, respiratory, and wound complications were also noted. RESULTS: Operative mortality was 2% in the SIMA group and 1.3% in the BIMA group (NS). Other than the prevalence of ventricular arrhythmias (P = 0.025), which were more common in the BIMA group, there were no significant differences between the two groups in terms of postoperative morbidity. At median (interquartile range) follow up of 27.94(0.86) and 23.94(0.74) months for the SIMA and BIMA groups respectively there were no deaths. 87% of the SIMA group and 91% of the BIMA group were free of symptoms at follow up. CONCLUSIONS: The earlier fears regarding increased early mortality and morbidity after BIMA surgery were not confirmed by this study. All patients receiving both mammary arteries had a free rather than pedicle right internal mammary graft. The early mortality and morbidity reported here compares favourably with previous reports on the use of a pedicle graft.

Adult↗

The international standard for atrial natriuretic factor. Calibration by an international collaborative study.

An ampouled preparation of human atrial natriuretic factor, ANF-(99-126), was evaluated by 23 laboratories in 10 countries for its suitability to serve as the international standard for ANF. The preparation was calibrated by radioimmunoassay, radioreceptor binding assay, and bioassay and was shown to have satisfactory stability and biological activity. Estimates of the ANF content of a set of specimens of plasma in terms of the standard showed agreement in ranking order when the ANF was extracted prior to assay. However, estimates of the ANF content of the plasmas in terms of either the international standard or the various local standards varied widely among laboratories. On the basis of the results reported here, with the agreement of the participants in the study and with the authorization of the Expert Committee on Biological Standardization of the World Health Organization, the preparation coded 85/669 was established in 1987 as the international standard for ANF, with a defined potency of 2.5 international units per ampoule.

Atrial Natriuretic Factor↗

Internalization and recycling of the C5a anaphylatoxin receptor: evidence that the agonist-mediated internalization is modulated by phosphorylation of the C-terminal domain.

The C5a anaphylatoxin receptor is a member of the G protein-coupled receptor family involved in chemoattraction and activation of myeloid cells, as well as in host defence against infection by Pseudomonas aeruginosa. Upon challenge by C5a, the C5a receptor undergoes a rapid phosphorylation on serine residues in the carboxyl-terminal region. In this study, we used cells stably transfected with either the wild-type C5a receptor, or mutants affected in their capacity to be phosphorylated, to examine the role played by phosphorylation in the intracellular trafficking of the C5a receptor. Upon agonist binding, the wild-type receptor was rapidly internalized into endosomes that cluster near the nucleus after 10 minutes. Internalization of a non-phosphorylable mutant was severely impaired relative to wild-type receptor, whereas a mutant phos-phorylated on serine 327 and/or serine 338, showed a rate of internalization intermediate between that of wild-type receptor and that of the non-phosphorylable mutant. Under continuous exposure to C5a and in the absence of protein synthesis, the C5a receptor was maintained in a highly phosphorylated state but was not degraded. Confocal microscopy and ligand-binding studies indicated that internalized receptors were recycled to the plasma membrane. During this process, receptors were dephosphorylated with kinetics that correlated with the kinetics of receptor recovery on the cell surface. Altogether, our data suggest that phosphorylation plays a key role in the intracellular trafficking of the C5a receptor. Phosphoryl-ated receptors might be recognized by an adaptor protein that interacts with the endocytic machinery.

Amino Acid Sequence↗

International rescue? The dynamics and policy implications of the international recruitment of nurses to the UK.

This paper focuses on one global aspect of the current health sector workforce policy agenda - the international recruitment and migration of health workers. It does so primarily by using a case study of the recruitment of nurses to the UK, as a means of exploring the policy challenges and associated research questions. The paper highlights the limitations in comparing national data on the nursing workforce, illustrating the extent to which currently collated national data can present a misleading picture of staff:population ratios in different countries. It then reports on the significant growth in the numbers of nurses entering the UK from other countries, using registration data. In 2001/02, more than 16 000 nurses entered the UK nursing register from non-UK sources. In this year, for the first time, the number exceeded the number of home-trained nurses. An analysis of postcode data highlights that these non-UK nurses have a younger age profile than home-based registered nurses and are more likely to report a postcode in London and south-east England. The paper also examines the push and pull factors that contribute to the international mobility of health workers. The paper concludes by examining the policy implications of this growing reliance on international recruitment, including the effect of the ethical guidelines on international recruitment introduced by the Department of Health in England.

Adult↗

The effects of internal radiation exposure on cancer mortality in nuclear workers at Rocketdyne/Atomics International.

We examined the effects of chronic exposure to radionuclides, primarily uranium and mixed-fission products, on cancer mortality in a retrospective cohort study of workers enrolled in the radiation-monitoring program of a nuclear research and development facility. Between 1950 and 1994, 2,297 workers were monitored for internal radiation exposures, and 441 workers died, 134 (30.4%) of them from cancer as the underlying cause. We calculated internal lung-dose estimates based on urinalysis and whole-body and lung counts reported for individual workers. We examined cancer mortality of workers exposed at different cumulative lung-dose levels using complete risk-set analysis for cohort data, adjusting for age, pay type, time since first radiation monitored, and external radiation. In addition, we examined the potential for confounding due to chemical exposures and smoking, explored whether external radiation exposure modifies the effects of internal exposure, and estimated effects after excluding exposures likely to have been unrelated to disease onset. Dose-response relations were observed for death from hemato- and lymphopoietic cancers and from upper aerodigestive tract cancers, adjusting for age, time since first monitored, pay type, and external (gamma) radiation dose. No association was found for other cancers, including cancers of the lung. Despite the small number of exposed deaths from specific cancer types and possible bias due to measurement error and confounding, the positive findings and strong dose-response gradients observed suggest carcinogenic effects of internal radiation to the upper aerodigestive tract and the blood and lymph system in this occupational cohort. However, causal inferences require replication of our results in other populations or confirmation with an extended follow-up of this cohort.

California↗

The international reference preparation of calcitonin, human, for bioassay: assessment of material and definition of the international unit.

An international reference material is required for bioassays of preparations of synthetic human calcitonin for administration to man and for use in immunoassays. A preparation of synthetic human calcitonin in ampoules coded 70/234 (previously widely used as the MRC Research Standard) has been examined in an international collaborative study involving 7 laboratories in 6 countries. The results of 34 in vivo bioassays with two other preparations of synthetic human calcitonin showed that this preparation was suitable to serve as a standard. With the agreement of the participants in the collaborative study, the batch of ampoules, code 70/234, was established in 1978 by the World Health Organization as the International Reference Preparation of Calcitonin, Human, for Bioassay. The International Unit of human calcitonin was defined as the activity contained in one ampoule of this preparation, thus maintaining continuity of the unit of the research standard.

Animals↗

Internal mammary artery subclavian vein fistula following internal jugular vein catheterization. A case report and review of the literature.

We have recently treated a patient with an arteriovenous fistula that developed after a right internal jugular vein catheterization. The patient was found to have a pulsatile hematoma and a bruit five days after removal of a temporary pacemaker catheter. Digital subtraction arteriography documented a fistula between the right internal mammary artery and subclavian vein. The fistula was surgically repaired via the cervical route. To our knowledge, an arteriovenous fistula between the internal mammary artery and subclavian vein has not been previously described as a complication of a percutaneous internal jugular vein catheterization.

Adult↗

Discontinuities in the internal elastic lamina: a comparison of coronary and internal mammary arteries.

The internal elastic lamina (iel.) of the anterior descending branch of the left coronary artery, and the internal mammary artery, were studied in 166 unselected subjects of different ages and races. The coronary artery showed substantial defects in the iel. even in the first few years of life, while the iel. of the mammary artery showed only minimal defects in all age groups. The defects in the iel. were associated with the presence of medial cells in the intima, and the thickness of the intima was correlated with the magnitude of the defects in the iel. (Correlation coefficient 0.95 for the coronary artery and 0.80 for the mammary artery). Small arteries involved in chronic inflammatory or neoplastic disease showed a similar relationship if the vessel were present in an edematous area. These vessels which do not usually show intimal thickening, displayed a thickened intima in the vicinity of defects of the iel. It is suggested that the pronounced difference in the incidence of arteriosclerosis between the coronary and internal mammary arteries is related to these defects in the internal elastic lamina.

Adolescent↗

Is international travel useful for general practitioners? A survey of international travel scholarships.

BACKGROUND: The Royal College of General Practitioners has offered international travel scholarships for the past decade. Each year a number of general practitioners travel from the UK to work or study assisted by the scheme, while others come to this country for similar purposes. AIM: To investigate the value of international scholarships for recipients and others. METHOD: All those receiving awards in 1988-94 were surveyed by postal questionnaire. RESULTS: Fifty-one out of 58 award winners (88%) replied. Almost all cited some of a wide variety of personal benefits from international travel, and some established continuing links with colleagues overseas. Many gave examples of useful results for others, both patients and colleagues. Scholarships appear to have made a significant contribution to careers, especially for those based outside Britain. CONCLUSION: Relatively modest travel scholarships were viewed both favourably in hindsight and produced a wide range of benefits to recipients, colleagues, and patients. International travel should probably be considered more widely in career planning.

Education, Medical, Continuing↗

International health and internal medicine residency training: the Duke University experience.

OBJECTIVE: To evaluate the impact of the Duke University Medicine Residency International Health Program (IHP) on program participants and to evaluate the relationship of the IHP to the residency program. SUBJECTS AND METHODS: The Duke University Medicine Residency Program classes of 1988 to 1996 participated in a questionnaire-based survey. All program participants (n = 59), a group of nonparticipants (n = 138), and residents who had not yet had an opportunity to participate (preparticipants; n = 106). RESULTS: The overall response rate to the questionnaire was 93%. Participation exceeded expectations and had a strongly positive impact on personal and professional lives of the majority of the participants. Participants reported a significant positive impact on their training in internal medicine and their knowledge of tropical medicine. A minority of nonparticipants identified a positive effect in these areas due to conferences and interactions with their participating colleagues. Participants who changes career plans during residency tended to move toward areas of general internal medicine or public health, in contrast to nonparticipants who tended to change areas of subspecialty or chose private practice. The IHP was identified as a significant factor for selection of the Duke Medicine Residency by 42% of the preparticipant group. Nearly all of the respondents (99%) indicated that the IHP should be continued. CONCLUSION: The IHP has a measurable positive impact on the participants, as well as on the Medicine Residency Program.

Career Choice↗

European Concerted Action on Anticoagulation. Correction of displayed international normalized ratio on two point-of-care test whole-blood prothrombin time monitors (CoaguChek Mini and TAS PT-NC) by independent international sensitivity index calibration.

The international normalized ratio (INR) on two widely used point-of-care test (POCT) prothrombin time (PT) monitors (CoaguChek Mini and TAS PT-NC) differed considerably and also differed from the 'true' INR obtained on the same samples using a manual PT and the same species thromboplastin international reference preparation. Agreement between the displayed INR and difference from 'true' INR has been reassessed following an independent international sensitivity index (ISI) calibration of the two systems. The displayed INRs taken at seven centres were compared with 'true' INRs from the same blood donations and INRs based on the resulting ISI. The overall difference between the displayed INRs on the two monitor systems was reduced from 21.0% to 3.5%. The overall difference in mean INR of system A from the 'true' INR was reduced from 19.0% to 9.5% and of system B from 6.8% to 0.3%, but individual centre's results still showed considerable mean INR variability. Differences between overall displayed INR with the two monitor systems have been reduced by an independent multicentre calibration, and agreement with 'true' INR on the same blood samples improved. However, marked variability in mean INR at individual centres remained after ISI correction, which demonstrates the need for external quality control of individual POCT whole-blood PT monitors.

Anticoagulants↗

International collaborative study for the calibration of a proposed international standard for thromboplastin, rabbit, plain.

BACKGROUND: A preparation of rabbit brain thromboplastin, provisionally coded 04/162, is proposed as a candidate for the World Health Organization (WHO) International Standard (IS) for thromboplastin (rabbit, plain), meant to replace the IS coded RBT/90 (rabbit, plain), stocks of which are now exhausted. RESULTS: The preparation was calibrated in an international collaborative study involving 21 laboratories from 13 countries and the calibration was performed against the existing WHO-IS (i.e. rTF/95 and OBT/79) and other Certified Reference Materials from the Institute for Reference Materials and Measurements of the European Commission (i.e. CRM149 S) and from the European Action on Anticoagulation (i.e. EUTHR-01). An additional candidate rabbit brain thromboplastin coded as 04/106 was also included in the study. On the basis of predefined criteria (the within- and between-laboratory precision of the calibration and the conformity to the calibration model), 04/162 was the preferred candidate. CONCLUSIONS: The assigned International Sensitivity Index value was 1.15 and the inter-laboratory SD and coefficient of variation were 0.057% and 4.9%, respectively.

Animals↗

Ethical considerations in international nursing research: a report from the International Centre for Nursing Ethics.

Ethical issues in international nursing research are identified and the perspectives o International Centre for Nursing Ethics are offered in an effort to develop an international consensus of ethical behaviour in research. First, theoretical issues are reviewed, then initial conditions for ethical conduct are defined, and protocol design and procedure considerations are examined. A concerted effort is made to identify and avoid a western bias. Broad guiding principles for designing and reviewing research are offered: (1) respect for persons; (2) beneficence; (3) justice; (4) respect for community; and (5) contextual caring. A collaborative model of the researcher-participant relationship is suggested and discussed.

Academies and Institutes↗