Paving the way for application of next generation risk assessment to safety decision-making for cosmetic ingredients.

Next generation risk assessment (NGRA) is an exposure-led, hypothesis-driven approach that has the potential to support animal-free safety decision-making. However, significant effort is needed to develop and test the in vitro and in silico (computational) approaches that underpin NGRA to enable confident application in a regulatory context. A workshop was held in Montreal in 2019 to discuss where effort needs to be focussed and to agree on the steps needed to ensure safety decisions made on cosmetic ingredients are robust and protective. Workshop participants explored whether NGRA for cosmetic ingredients can be protective of human health, and reviewed examples of NGRA for cosmetic ingredients. From the limited examples available, it is clear that NGRA is still in its infancy, and further case studies are needed to determine whether safety decisions are sufficiently protective and not overly conservative. Seven areas were identified to help progress application of NGRA, including further investments in case studies that elaborate on scenarios frequently encountered by industry and regulators, including those where a 'high risk' conclusion would be expected. These will provide confidence that the tools and approaches can reliably discern differing levels of risk. Furthermore, frameworks to guide performance and reporting should be developed.

Safe management of surgical smoke in the age of COVID-19.

BACKGROUND: The COVID-19 global pandemic has resulted in a plethora of guidance and opinion from surgical societies. A controversial area concerns the safety of surgically created smoke and the perceived potential higher risk in laparoscopic surgery. METHODS: The limited published evidence was analysed in combination with expert opinion. A review was undertaken of the novel coronavirus with regards to its hazards within surgical smoke and the procedures that could mitigate the potential risks to healthcare staff. RESULTS: Using existing knowledge of surgical smoke, a theoretical risk of virus transmission exists. Best practice should consider the operating room set-up, patient movement and operating theatre equipment when producing a COVID-19 operating protocol. The choice of energy device can affect the smoke produced, and surgeons should manage the pneumoperitoneum meticulously during laparoscopic surgery. Devices to remove surgical smoke, including extractors, filters and non-filter devices, are discussed in detail. CONCLUSION: There is not enough evidence to quantify the risks of COVID-19 transmission in surgical smoke. However, steps can be undertaken to manage the potential hazards. The advantages of minimally invasive surgery may not need to be sacrificed in the current crisis.

Developments in understanding and applying prebiotics in research and practice-an ISAPP conference paper.

AIMS: The concept of using specific dietary components to selectively modulate the gut microbiota to confer a health benefit, defined as prebiotics, originated in 1995. In 2018, a group of scientists met at the International Scientific Association for Probiotics and Prebiotics annual meeting in Singapore to discuss advances in the prebiotic field, focussing on issues affecting functionality, research methodology and geographical differences. METHODS AND RESULTS: The discussion ranged from examining scientific literature supporting the efficacy of established prebiotics, to the prospects for establishing health benefits associated with novel compounds, isolated from different sources. CONCLUSIONS: While many promising candidate prebiotics from across the globe have been highlighted in preliminary research, there are a limited number with both demonstrated mechanism of action and defined health benefits as required to meet the prebiotic definition. Prebiotics are part of a food industry with increasing market sales, yet there are great disparities in regulations in different countries. Identification and commercialization of new prebiotics with unique health benefits means that regulation must improve and remain up-to-date so as not to risk stifling research with potential health benefits for humans and other animals. SIGNIFICANCE AND IMPACT OF STUDY: This summary of the workshop discussions indicates potential avenues for expanding the range of prebiotic substrates, delivery methods to enhance health benefits for the end consumer and guidance to better elucidate their activities in human studies.

Comparison of recovery and outcome after left and right colectomy.

AIM: The present study aimed to compare functional recovery and surgical outcomes after left and right colectomies. METHOD: Consecutive elective left and right colon resections for benign and malignant indications, performed between 2011 and 2016 and recorded in a prospectively maintained enhanced recovery database, were analysed. Demographic and surgical items, as well as functional recovery and 30-day complications, were compared between left-sided and right-sided colectomies. Multivariable analysis was performed to identify risk factors for postoperative ileus (POI). RESULTS: In total, 1001 left and 1041 right colectomies were comparable regarding demographic factors; only body mass index (BMI) was higher in patients undergoing left-sided resections (> 30 kg/m2 : 33% vs 27%, P = 0.004). Malignancy (29% vs 67%, P < 0.001) and Crohn's disease (1% vs 31%, P < 0.001) were preponderant in right colectomies, whereas diverticular disease (68% vs 1%, P < 0.001) was the most common indication for left colectomy. Compliance with the enhanced recovery pathway (ERP) was comparable. While the minimally invasive approach was the preferred approach for both sides (61% vs 64%, P = 0.158), left colectomies took longer (180 ± 80 min vs 150 ± 70 min, P < 0.001), needed more perioperative fluids (3.1 ± 1.4 l vs 2.7 ± 1.5 l, P < 0.001) and resulted in greater postoperative weight gain (3.9 ± 6.5 kg vs 2.6 ± 6 kg, P = 0.025). Crohn's disease (OR = 2.64, 95% CI: 1.27-5.46) and fluid overload (OR = 2.02, 95% CI: 1.06-3.82) were independent risk factors for POI. CONCLUSION: Despite equal ERP compliance, postoperative ileus was higher after right-sided colectomies. This finding was associated with Crohn's disease and fluid overload.

A systematic review of Clostridium difficile infection following reversal of ileostomy.

AIM: The incidence of Clostridium difficile infection (CDI) has been reported to be as high as 4% following ileostomy reversal. CDI can be associated with significant morbidity. A systematic review on this subject has not been previously reported; our aim was to review the literature to establish incidence and to evaluate the factors that may contribute to an increased risk of CDI following ileostomy reversal. METHOD: A systematic review of Ovid, Embase and Medline was undertaken. Search terms included C. difficile, reversal of ileostomy and ileostomy closure. Articles were included where at least one case of C. difficile-associated diarrhoea following reversal of defunctioning ileostomy was reported. Data extraction for articles was performed by two authors, using predefined data fields. The primary outcome measure was incidence of CDI amongst patients undergoing ileostomy reversal. Secondary outcomes were defunctioning time, antibiotic regime, acid suppression, time to onset of symptoms and study conclusions including colectomy and mortality rate. RESULTS: Eleven articles were included (five case reports and six cohort studies). The overall incidence of CDI was 1.8% (242/13 728). The mean defunctioning time was 8.7 months (range 6-12). A variety of antibiotic regimes were described. Mean time to onset of symptoms was 6 days (range 3-14). Use of acid suppression, colectomy or mortality rate were frequently not reported. CONCLUSION: CDI should be recognized as a potentially life-threatening complication of ileostomy closure. Careful consideration should be given to peri-operative antibiotic regime, acid suppression, timing of reversal and appropriate preoperative counselling of patients.

The WIMAT colonoscopy suitcase model: a novel porcine polypectomy trainer.

AIM: Simulation allows the acquisition of complex skills within a safe environment. Endoscopic polypectomy has a long learning curve. Our novel polypectomy simulator may be a useful adjunct for training. The aim of this study was to assess its content validity. METHOD: The Welsh Institute for Minimal Access Therapy (WIMAT) endoscopy suitcase was designed to simulate colonic polypectomy. Participants from regional and national courses were recruited into the study. Each undertook a standardized simulated polypectomy and completed a seven-point Likert scale questionnaire examining its realism. RESULTS: In all, 17 participants completed the questionnaire: 15 (88.2%) gastroenterologists, one (5.9%) colorectal surgeon and one (5.9%) experienced endoscopic nurse specialist. Of the gastroenterologists, seven (46.7%) were consultants and eight (53.3%) were senior trainees or Post CCT (Certificate of Completion of Training) fellows. The mean number of real-life polypectomies performed by the cohort was 156 (95% CI 35-355). The highest scores were for 'mucosal realism' (median score 6.0, P=0.001), 'endoscopic snare control' (median score 6.0, P=0.001), 'handling the polyp' (median score 6.0, P=0.001) and 'raising mucosa' (median score 6.0, P<0.001). Of the 15 parameters examined only three were not statistically significant in favour of the simulator. These were 'anatomical realism of sessile polyps', 'resistance of scope movement' and 'paradoxical motion'. The overall score for the simulation was 6.0 (P < 0.001). There was no significant difference between the level of difficulty of the simulator compared with real life (median score 4.0, P = 0.559). CONCLUSION: The WIMAT colonoscopy suitcase model has excellent content validity for several parameters. This may have potential applications in medical training and assessment.

DNA ligase I is required for fetal liver erythropoiesis but is not essential for mammalian cell viability.

Four distinct DNA ligase activities (I-IV) have been identified within mammalian cells. Evidence has indicated that DNA ligase I is central to DNA replication, as well as being involved in DNA repair processes. A patient with altered DNA ligase I displayed a phenotype similar to Bloom's syndrome, being immunodeficient, growth retarded and predisposed to cancer. Fibroblasts isolated from this patient (46BR) exhibited abnormal lagging strand synthesis and repair deficiency. It has been reported that DNA ligase I is essential for cell viability, but here we show that cells lacking DNA ligase I are in fact viable. Using gene targeting in embryonic stem (ES) cells, we have produced DNA ligase I-deficient mice. Embryos develop normally to mid-term when haematopoiesis usually switches to the fetal liver. Thereupon acute anaemia develops, despite the presence of erythroid-committed progenitor cells in the liver. Thus DNA ligase I is required for normal development, but is not essential for replication. Hence a previously unsuspected redundancy must exist between mammalian DNA ligases.

Safety of maintaining elective and emergency surgery during the COVID-19 pandemic with the introduction of a Protected Elective Surgical Unit (PESU): A cross-specialty evaluation of 30-day outcomes in 9,925 patients undergoing surgery in a University Health Board.

Background: The COVID-19 pandemic has caused unprecedented health care challenges mandating surgical service reconfiguration. Within our hospital, emergency and elective streams were separated and self-contained Protected Elective Surgical Units were developed to mitigate against infection-related morbidity. Aims of this study were to determine the risk of COVID-19 transmission and mortality and whether the development of Protected Elective Surgical Units can result in significant reduction in risk. Methods: A retrospective observational study of consecutive patients from 18 specialties undergoing elective or emergency surgery under general, spinal, or epidural anaesthetic over a 12-month study period was undertaken. Primary outcome measures were 30-day postoperative COVID-19 transmission rate and mortality. Secondary adjusted analyses were performed to ascertain hospital and Protected Elective Surgical Unit transmission rates. Results: Between 15 March 2020 and 14 March 2021, 9,925 patients underwent surgery: 6,464 (65.1%) elective, 5,116 (51.5%) female, and median age 57 (39-70). A total of 69.5% of all procedures were performed in Protected Elective Surgical Units. Overall, 30-day postoperative COVID-19 transmission was 2.8% (3.4% emergency vs 1.2% elective P < .001). Protected Elective Surgical Unit postoperative transmission was significantly lower than non-Protected Elective Surgical Unit (0.42% vs 3.2% P < .001), with an adjusted likely in-hospital Protected Elective Surgical Unit transmission of 0.04%. The 30-day all-cause mortality was 1.7% and was 14.6% in COVID-19-positive patients. COVID-19 infection, age > 70, male sex, American Society of Anesthesiologists grade > 2, and emergency surgery were all independently associated with mortality. Conclusion: This study has demonstrated that Protected Elective Surgical Units can facilitate high-volume elective surgical services throughout peaks of the COVID-19 pandemic while minimising viral transmission and mortality. However, mortality risk associated with perioperative COVID-19 infection remains high.

The control of microvascular permeability and blood pressure by neutral endopeptidase.

Plasma extravasation from postcapillary venules is one of the earliest steps of inflammation. Substance P (SP) and bradykinin (BK) mediate extravasation and cause hypotension. The cell-surface enzyme neutral endopeptidase (NEP) inactivates both peptides. Thus, absence of NEP may predispose development of inflammation and hypotension. We examined these possibilities in mice in which the NEP gene was deleted by homologous recombination. There was widespread basal plasma extravasation in postcapillary venular endothelia in NEP-/- mice, which was reversed by recombinant NEP and antagonists of SP (NK1) and BK (B2) receptors. Mean arterial blood pressure was 20% lower in NEP-/- animals, but this was unaffected by reintroduction of recombinant NEP and the kinin receptor antagonists. The hypotension was also independent of nitric oxide (NO), because NEP-/- mice treated with a NO synthase inhibitor remained hypotensive relative to the wild type. Thus, NEP has important roles in regulating basal microvascular permeability by degrading SP and BK, and may regulate blood pressure set point through a mechanism that is independent of SP, BK and NO. The use of NEP antagonists as candidate drugs in cardiovascular disease is suggested by the blood pressure data reported herein.

Development of B lymphocytes in mice heterozygous for the X-linked immunodeficiency (xid) mutation. xid inhibits development of all splenic and lymph node B cells at a stage subsequent to their initial formation in bone marrow.

CBA/N mice were crossed with CBA/Ca-Pgk-1a to produce female F1 hybrids that were heterozygous for both xid and the phosphoglycerate kinase 1 (PGK-1) allozymes. PGK acted as a quantifiable marker for the frequency of cells in which the xid-bearing X chromosome was active in lymphocytic and other cell populations. In adults, such cells (termed xid cells) were virtually absent in FACS-sorted splenic and lymph node B cells, and in all three splenic subpopulations distinguished on the basis of their relative expression of membrane mu and delta chains. Thus, the xid mutation appeared to compromise the development of all B cells. Erythrocytes, thymocytes, T cells, and granulocytes were unaffected. Selection against xid cells was less pronounced in the spleens of 2-6-wk-old mice. In the bone marrow, there was evidence for selection against xid in the production of B cells (except at 2 wk of age), but not at the pre-B cell level. These data suggest that, in competition with normal non-xid cells, newly-formed xid B cells were less likely to be incorporated into the peripheral B cell pool.

Facing the Ethical Challenges: Consumer Involvement in COVID-19 Pandemic Research.

Consumer involvement in clinical research is an essential component of a comprehensive response during emergent health challenges. During the COVID-19 pandemic, the moderation of research policies and regulation to facilitate research may raise ethical issues. Meaningful, diverse consumer involvement can help to identify practical approaches to prioritize, design, and conduct rapidly developed clinical research amid current events. Consumer involvement might also elucidate the acceptability of flexible ethics review approaches that aim to protect participants whilst being sensitive to the challenging context in which research is taking place. This article describes the main ethical challenges arising from pandemic research and how involving consumers and the community could enable resolution of such issues.

Variation in training requirements within general surgery: comparison of 23 countries.

Background: Many differences exist in postgraduate surgical training programmes worldwide. The aim of this study was to provide an overview of the training requirements in general surgery across 23 different countries. Methods: A collaborator affiliated with each country collected data from the country's official training body website, where possible. The information collected included: management, teaching, academic and operative competencies, mandatory courses, years of postgraduate training (inclusive of intern years), working-hours regulations, selection process into training and formal examination. Results: Countries included were Australia, Belgium, Canada, Colombia, Denmark, Germany, Greece, Guatemala, India, Ireland, Italy, Kuwait, the Netherlands, New Zealand, Russia, Saudi Arabia, South Africa, South Korea, Sweden, Switzerland, UK, USA and Zambia. Frameworks for defining the outcomes of surgical training have been defined nationally in some countries, with some similarities to those in the UK and Ireland. However, some training programmes remain heterogeneous with regional variation, including those in many European countries. Some countries outline minimum operative case requirement (range 60-1600), mandatory courses, or operative, academic or management competencies. The length of postgraduate training ranges from 4 to 10 years. The maximum hours worked per week ranges from 38 to 88 h, but with no limit in some countries. Conclusion: Countries have specific and often differing requirements of their medical profession. Equivalence in training is granted on political agreements, not healthcare need or competencies acquired during training.

Antecedentes: Existen muchas diferencias entre los programas de formación quirúrgica de posgrado del mundo. El objetivo de este estudio fue proporcionar una visión general de los requisitos formativos en cirugía general en 23 países diferentes. Métodos: En cada uno de los países participantes, un colaborador recopiló datos de la página web del organismo oficial encargado de la formación, si era posible. La información incluyó: gestión, formación, competencias académicas y operatorias, cursos obligatorios, años de formación de postgrado (que incluía el período de internado), regulaciones sobre las horas de trabajo, proceso de selección para la formación y existencia de un examen final. Resultados: Se incluyeron los datos de Australia, Bélgica, Canadá, Colombia, Dinamarca, Alemania, Grecia, Guatemala, India, Irlanda, Italia, Kuwait, Países Bajos, Nueva Zelanda, Rusia, Arabia Saudita, Sudáfrica, Corea del Sur, Suecia, Suiza, Reino Unido, Estados Unidos de América y Zambia. En algunos países existen los marcos normativos para definir los resultados del programa de formación, con ciertas semejanzas a los del Reino Unido e Irlanda. Sin embargo, algunos programas de formación, incluso en muchos países europeos, son muy heterogéneos con variaciones regionales. Pocos países describen el número mínimo de procedimientos quirúrgicos (rango 60 a 1.600), los cursos obligatorios o competencias quirúrgicas, académicos o de gestión exigidos. La duración de la formación postgraduada osciló de los 4 a los 10 años. El número de horas trabajadas máximas por semana oscilaron entre 38 y 88, sin límite en algunos países. Conclusión: Cada país tiene unos requisitos específicos, a menudo diferentes, para la formación de sus médicos. La convalidación se otorga por acuerdos políticos, más que por las necesidades médicas o por las competencias adquiridas durante la formación.

Factor Xa or thrombin: is factor Xa a better target?

Existing vitamin K antagonists (VKAs) have drawbacks that limit their effectiveness, safety, and overall frequency of use. Oral anticoagulants in development with targeted action against individual coagulation factors, specifically direct factor (F) Xa and IIa inhibitors, appear to have pharmacokinetic and pharmacodynamic properties that overcome the limitations of the VKAs. Based on the theory of how coagulation factors interact, on the results of in vitro studies, and on clinical outcomes, there is accumulating evidence that FXa may represent a better target for inhibition than FIIa. This is based on an understanding of the amplified nature of coagulation factor interactions and fibrin formation, the need for smaller doses of an anticoagulant to block coagulation progression earlier in the sequence of reactions, the evidence for incomplete suppression of thrombin generation with direct thrombin inhibitors, evidence for rebound hypercoagulability with thrombin inhibitors, and clinical results with the indirect, parenteral, FXa inhibitor (fondaparinux), as well as early phase II results of new oral Xa and IIa inhibitors compared with enoxaparin. The latter studies, although not comparative, provide some evidence for the effectiveness and safety of Xa inhibitors at a range of doses not seen with the direct IIa inhibitors.

The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.

BACKGROUND: Heparins and warfarin are currently used as venous thromboembolism (VTE) prophylaxis in surgery. Inhibition of factor (F) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit-risk profile. OBJECTIVES: To evaluate the safety and efficacy of apixaban, a potent, direct, oral inhibitor of FXa, in patients following total knee replacement (TKR), and to investigate dose-response relationships. PATIENTS/METHODS: A total of 1238 patients were randomized to one of six double-blind apixaban doses [5, 10 or 20 mg day(-1) administered as a single (q.d.) or a twice-daily divided dose (b.i.d.)], enoxaparin (30 mg b.i.d.) or open-label warfarin (titrated to an International Normalized Ratio of 1.8-3.0). Treatment lasted 10-14 days, commencing 12-24 h after surgery with apixaban or enoxaparin, and on the evening of surgery with warfarin. The primary efficacy outcome was a composite of VTE (mandatory venography) and all-cause mortality during treatment. The primary safety outcome was major bleeding. RESULTS: A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis. All apixaban groups had lower primary efficacy event rates than either comparator. The primary outcome rate decreased with increasing apixaban dose (P = 0.09 with q.d./b.i.d. regimens combined, P = 0.19 for q.d. and P = 0.13 for b.i.d. dosing).A significant dose-related increase in the incidence of total adjudicated bleeding events was noted in the q.d. (P = 0.01) and b.i.d. (P = 0.02) apixaban groups; there was no difference between q.d. and b.i.d. regimens. CONCLUSIONS: Apixaban in doses of 2.5 mg b.i.d. or 5 mg q.d. has a promising benefit-risk profile compared with the current standards of care following TKR.

Glutathione and glutathione transferase levels in mouse granulocytes following cyclophosphamide administration.

Following an initial depletion, glutathione and glutathione transferase levels are transiently increased in mouse bone marrow following the administration of a low dose of cyclophosphamide. Similar effects are observed on subsequent administration of the drug. The separation of various bone marrow populations on a fluorescence-activated cell sorter has shown that increase in glutathione and glutathione transferase levels are restricted to the granulocytic fraction. This may well provide an explanation for the protective effect of a low 'priming' dose of cyclophosphamide against a subsequent lethal dose. The changes in granulocytic glutathione and glutathione transferase levels can also be monitored in the peripheral circulation. The enhanced levels of glutathione in cells resulting from cytotoxic insult appear to be a general response of cells to cytotoxins and may be important in both antitumor therapy as well as the initiation of chemical toxicity and carcinogenicity.

Modular emergency general surgery training: A pilot study of a novel programme.

Introduction Pan-speciality consensus guidance advocates mandatory emergency general surgery (EGS) training modules for specialist registrars (StRs). This pilot study evaluated the impact of EGS modules aimed at StRs over 1 year. Methods Eleven StRs were allocated a focused 4-week EGS module, in addition to the standard 1:12 on-call duty rota, in a tertiary surgical centre. Primary outcome measures included the number of indicative emergency operations and validated Procedure Based Assessments (PBAs) performed, both during the EGS module and over the training year. Results StRs performed a median of 11 (range 5-15) laparotomies during the EGS module versus 31 (range 9-49) over the whole training year. StRs attended 43.7% of available laparotomies during the module (range 24.1-63.7%). EGS modules provided more than one-third of the total emergency laparotomy experience, and a quarter of the emergency colectomy, appendicectomy and Hartmann's procedure experience. There were no differences in EGS module-related outcomes between junior and senior StRs. Significantly more PBAs related to laparotomy and segmental colectomy were completed during EGS modules than the on-call duty rota, at 32% versus 14% (p<0.001) and 48% versus 22% (p=0.019), respectively. Performance levels were maintained following module completion. Conclusions These findings provide an important baseline when considering future modular EGS training.

Hughes Abdominal Repair Trial (HART) - Abdominal wall closure techniques to reduce the incidence of incisional hernias: study protocol for a randomised controlled trial.

BACKGROUND: Incisional hernias are common complications of midline closure following abdominal surgery and cause significant morbidity, impaired quality of life and increased health care costs. The 'Hughes Repair' combines a standard mass closure with a series of horizontal and two vertical mattress sutures within a single suture. This theoretically distributes the load along the incision length as well as across it. There is evidence to suggest that this technique is as effective as mesh repair for the operative management of incisional hernias; however, no trials have compared the Hughes Repair with standard mass closure for the prevention of incisional hernia formation following a midline incision. METHODS/DESIGN: This is a 1:1 randomised controlled trial comparing two suture techniques for the closure of the midline abdominal wound following surgery for colorectal cancer. Full ethical approval has been gained (Wales REC 3, MREC 12/WA/0374). Eight hundred patients will be randomised from approximately 20 general surgical units within the United Kingdom. Patients undergoing open or laparoscopic (more than a 5-cm midline incision) surgery for colorectal cancer, elective or emergency, are eligible. Patients under the age of 18 years, those having mesh inserted or undergoing musculofascial flap closure of the perineal defect in abdominoperineal wound closure, and those unable to give informed consent will be excluded. Patients will be randomised intraoperatively to either the Hughes Repair or standard mass closure. The primary outcome measure is the incidence of incisional hernias at 1 year as assessed by standardised clinical examination. The secondary outcomes include quality of life patient-reported outcome measures, cost-utility analysis, incidence of complete abdominal wound dehiscence and C-POSSUM scores. The incidence of incisional hernia at 1 year, assessed by computerised tomography, will form a tertiary outcome. DISCUSSION: A feasibility phase has been completed. The results of the study will be used to inform current and future practice and potentially reduce the risk of incisional hernia formation following midline incisions. TRIAL REGISTRATION NUMBER: ISRCTN 25616490 . Registered on 1 January 2012.

Differentiation and delayed cell death in embryonal stem cells exposed to low doses of ionising radiation.

Embryonal stem cells have been used to study the effects of environmentally relevant doses of radiation on cell death and differentation. The ES cells were found to have a greater than 60% chance of surviving the traversal of a single alpha-particle, the lowest possible dose of high linear energy transfer radiation a cell may receive. The ES cells appeared to possess the cell cycle checkpoints believed to prevent the transmission of the radiation damage. However, delayed effects were observed in the progeny. An increased incidence of apoptosis and haempoietic differentiation capacity was found to persist in the ES cell population over many cell divisions. Since both cell death and differentiation are known to play a key role in tissue kinetics, an ES cell model will provide a valuable and versatile cell system for studying the role of cell death and differentiation in the pathology of radiogenic diseases.

Oral anticoagulant therapy--50 years later.

The year 1991 marked the 50th anniversary of the first clinical use of oral anticoagulant therapy as a means of preventing thromboembolic disease. Despite long-term physician familiarity with oral anticoagulants, this mode of therapy still suffers from a relatively high-risk/safety profile. This review briefly highlights important historical and pharmacokinetic points of interest but focuses predominantly on aspects of the day-to-day management of anticoagulant therapy aiming to enhance physician performance in this therapeutic milieu. Emphasis is placed on therapeutic monitoring, understanding the prothrombin time, managing complications, and assessing future innovations for the management of a growing population of patients treated with orally administered anticoagulants.