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PubMed2017

Rapid DNA replication origin licensing protects stem cell pluripotency.

Complete and robust human genome duplication requires loading minichromosome maintenance (MCM) helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single-cell analyses, we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation toward all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance.

Cell Cycle↗
PubMed2003

Vaccination coverage among children enrolled in Head Start programs, licensed child care facilities, and entering school--United States, 2000-01 school year.

The implementation of state and local requirements for vaccination before entry to Head Start programs, licensed child care facilities, and school has resulted in high vaccination levels among preschool and school children. One of the national health objectives for 2010 is to maintain > or = 95% vaccination coverage among children attending licensed child care centers and kindergarten through postsecondary school (objective 12-23). National estimates of vaccination coverage among children in Head Start programs, licensed child care facilities, and those entering school have been published each year since 1997 on the basis of reports from federally funded immunization programs (IPs) in the 50 states, five cities, eight territories, and the District of Columbia. This report summarizes data reported by states, cities, and the District of Columbia for the 2000-01 school year. Although vaccination coverage for 2000-01 appears similar to that for previous years, the number of programs reporting and the completeness of the reports are lower than in previous years and do not permit precise estimation of coverage at the national level. IPs use school data to identify undervaccinated children enrolled in Head Start programs, licensed child care facilities, and those entering school; evaluate the success of prevention programs targeting these children; and document the proportion of children whose parents claim exemptions from one or more vaccines. Plans are ongoing to assist IPs in applying successful strategies for collecting, reporting, and increasing the precision of coverage estimates for these populations.

Child↗
PubMed2003

The role of the replication licensing system in cell proliferation and cancer.

The precise duplication of chromosomal DNA during each cell cycle is essential for the maintenance of genetic stability. Failure to correctly regulate chromosomal DNA replication could lead to losses or duplication of chromosome segments. The precise duplication of chromosomes is normally achieved by correct regulation of the replication licensing system. Here we review our current knowledge of the licensing system and how this might be defective in cancer cells. We also review how detection of licensing components can be used for the diagnosis and prognosis of cancer. Finally we discuss the potential of the replication licensing system as a novel anti-cancer target.

Animals↗
PubMed2004

[Driving license of patients with epilepsy, management of their oral drugs and suppositories by non-medical professionals, and the role of pediatric neurologists].

In June 2002, the following new driving regulations were enforced in Japan: 1. A person with epilepsy may be granted a driving license after a seizure-free period of two years. 2. A person with simple partial seizures that would not impair driving safety may be granted a driving license if no other seizures that may impair driving safety have occurred over a period of at least one year. 3. A person with seizures occurring only in sleep may be granted a driving license if no seizures have occurred in waking over a period of at least two years. 4. In case that the above requirements are going to be met within 6 months, driving should be prohibited for 6 months. 5. A person with epilepsy is recommended to apply for a license to drive heavy and/or public vehicles only after a seizure-free period of 5 years without medication. The committee for legal problems of the Japan Epilepsy Society proposed a guideline for non-medical teaching or caring professionals to give children with epilepsy antiepileptic medication or to insert suppositories, if needed, at schools or care institutions. The guideline indicated the following preconditions as important: 1. There must be a wish and consent of the patient or his/her family. 2. Drugs or suppositories are usually taken or used at home and regarded as a safe procedure. 3. Attending doctor should provide clear information about the use and risk of the medication or suppository. 4. Privacy of the patient should be protected. Pediatric neurologists are expected to play an important role on these issues.

Anticonvulsants↗
PubMed2005

Graduated driver licensing in Wisconsin: does it create safer drivers?

OBJECTIVES: The purpose of this study was to measure the effectiveness of Wisconsin's graduated driver licensing law and determine whether a reduction in crash rates was due to reduced exposure, safer driving, or both. METHODS: General population crash rates for 16 and 17 year olds were computed for years before and after graduated drivers licensing. The induced exposure method was used to measure exposure and compute the odds ratio of at-fault crash involvement. RESULTS: For 16 year olds, general crash rates declined 13.8% while injury crash rates declined 15.6%. For 17 year olds, crash rates declined 6.2% for all crashes and 5.8% for injury crashes. There was no statistically significant change in the odds ratio of at-fault crash involvement for 16- or 17-year-old drivers, relative to the reference group. After graduated drivers licensing, 16-year-old drivers were more likely to have at least 1 adult present and less likely to carry 2 or more teen passengers. There was no statistically significant effect on driving habits by time for 16 year olds. CONCLUSIONS: Graduated driver licensing in Wisconsin has resulted in a drop in the general population crash rates for 16 and 17 year olds. This decrease is the result of reduced exposure to the risk of collision rather than safer driving by teens.

Accidents, Traffic↗
PubMed2006

Factors associated with high-severity disciplinary action by a state medical board: a Texas study of medical license revocation.

CONTEXT: There has been an increase in research evaluating factors associated with disciplinary action of physicians by state medical boards. However, factors related to the severity of disciplinary action are lacking. By investigating these factors while controlling for the type of violation, the authors sought to determine whether physician characteristics influenced the process of disciplinary action by state medical boards. METHODS: Physicians disciplined by the Texas Medical Board between January 1, 1989, and December 31, 1998, were included in this case-controlled study (N=1129). Multivariate logistic regression analysis was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with license revocation, the most severe disciplinary action, compared with all other forms of disciplinary action combined. RESULTS: Anesthesiologists (OR, 2.45; 95% CI, 1.05-5.74), general practitioners (OR, 1.80; 95% CI, 1.01-3.19), and psychiatrists (OR, 2.68; 95% CI, 1.41-5.13), as well as those with multiple disciplinary actions (OR, 1.91; 95% CI, 1.29-2.83) were most susceptible to license revocation. The more years a disciplined physician was in practice, the greater risk he or she had of license revocation (OR, 1.05; 95% CI, 1.04-1.07). CONCLUSIONS: Factors associated with a greater likelihood of license revocation for physicians are: primary medical specialty, number of years in practice, and a history of multiple disciplinary actions.

Adult↗
PubMed2006

Cultural self-efficacy of licensed registered nurses in New Mexico.

This study determined the level of cultural self-efficacy of licensed Registered Nurses caring for multiethnic patients (White non-Hispanic, Hispanic, African American Native American and Asian American) in New Mexico, and the level of influence of various background and demographic variables. The sample consisted of 1000 randomly selected New Mexico licensed RNs. The Cultural Self-Efficacy Scale, developed by Bernal and Froman (1987), was modified and used to measure the confidence level of the licensed Registered Nurses. It is a 25-item Likert-type scale that groups cultural self-efficacy ratings into three categories: (a) knowledge of cultural concepts; (b) self-efficacy in performing cultural nursing skills; and (c) knowledge of cultural life patterns for specific ethnic groups. The data show that RNs in New Mexico are moderately efficacious in caring for patients/clients of cultures other than their own. Few demographic variables (age, number ofyears an RN) correlated with higher cultural self-efficacy levels. This study provided information on practicing nurses in New Mexico which, to date, was non-existent. Licensed Registered Nurses in New Mexico are moderately efficacious in caring for patients of five cultural/ethnic groups.

Adult↗
PubMed1995

Relationship between driver's license renewal policies and fatal crashes involving drivers 70 years or older.

OBJECTIVE: To assess the relationship between state driver's license renewal policies and fatal crashes involving drivers aged 70 years or older (seniors). DESIGN AND ANALYSIS: Poisson regression methods were used to isolate the relationship between different state policies mandating vision tests, knowledge tests, or road tests for driver's license renewal and fatal crashes involving senior drivers. The analysis controlled for differences among states, other than their renewal policies, likely to influence senior motor vehicle crashes. SETTING: United States, 1985 through 1989. PARTICIPANTS: All fatal crashes identified in the National Highway Traffic Safety Administration Fatal Accident Reporting System involving at least one driver aged 70 years or older. MAIN OUTCOME MEASURE: The number of fatal crashes per state in which at least one of the drivers was aged 70 years or older. When a single fatal crash involved more than one senior driver, each was included. RESULTS: State-mandated tests of visual acuity, adjusted for license renewal period, were associated with lower fatal crash risk for senior drivers (relative risk, 0.93; 95% confidence interval, 0.89 to 0.97). Knowledge tests, when added to vision tests and applied only to seniors, provided a nonsignificant reduction in the senior fatal crash risk (relative risk, 0.91; 95% confidence interval, 0.79 to 1.05). CONCLUSION: Tests of vision and knowledge for senior drivers at license renewal merit further attention as a means of improving senior traffic safety.

Accidents, Traffic↗
PubMed1993

[Revoking the driver's license, assessment of driver competence, re-education and therapy in alcohol offenses: approaches to a necessary reorientation].

After representing figures and facts about drinking behaviour and drinking-driving offences of the 45 mio. drivers in Germany counter-measures for DWI-offenders are dealt with. The proceedings practised so far are critically analysed and new approaches are discussed. Primarily reviewed are special preventive measures and here particularly the selection procedure usually applied in Germany, in which on demand of the driver licensing authorities the question is to be answered by expert opinions whether there is to be reckoned with driving under the influence in die future, too. It is pointed out that the expert opinions are not valid enough for making a distinct decision in an individual case. Validity coefficients obtained in evaluation studies lie between phi = 0 and .28, raising the expectancy value of 50% resulting by chance at best only on to 65%. Moreover the psychological interview is understandably burdened with faked answers of the explored person, in several cases increased by a specific, professionally managed preparation for the testing situation. As a way out of the dilemma expert opinions prognosticating driver behaviour should be waived in favour of making diagnoses and proposals for treatment. The timing of regranting the driver license is then only determined by the revocation period pronounced by the court and by the performance of the measures recommended by the experts and demanded by the licensing authority. As a support for such a procedure a more consistent and resolute administration of the judicial revocation of driver license with longer periods for repeaters should be provided. Besides there is necessary a wider range of rehabilitation programs for drivers with alcoholic problems.

Accidents, Traffic↗
PubMed1997

An evaluation of the effectiveness of alcohol treatment, driver license actions and jail terms in reducing drunk driving recidivism in California.

AIM: There has been long-standing interest in determining which sanctions work best to reduce drunk driving. This study examines the effectiveness of alcohol treatment, driver license actions and jail terms in reducing drunk-driving recidivism. DESIGN: This quasi-experimental study examines the relationships between the sanctions that drivers convicted of driving-under-the-influence (DUI) receive and their subsequent reconviction of DUI, while statistically controlling for pre-existing differences among groups receiving different sanctions. Separate analyses were conducted for subjects having 0, 1 or 2 or more prior DUI convictions on their driving record. SETTING: The study analyzes drunk driving reacidivism throughout the state of California. Participants. All drivers holding a California driver license who were convicted of DUI by a California court during 1990 and 1991 were selected for inclusion in the study. MEASUREMENTS: A number of demographic, prior personal driving history and surrogate traffic environment measures were collected and used as covariates in the analyses. Data were also gathered on subsequent DUI reconvictions, and the number of days to first subsequent DUI reconviction, and used as outcome variables in the study. FINDINGS: Results of the analyses showed that for all levels of prior DUI convictions, combining alcohol treatment with either driver license restriction or suspension is associated with the lowest DUI recidivism rates. CONCLUSIONS: Based on this research, and the results of prior studies, it can be persuasively argued that combining license actions with alcohol treatment represents the most effective sanction combination for combating DUI recidivism.

Alcohol Drinking↗
PubMed1998

Effectiveness and role of driver education and training in a graduated licensing system.

Formal driver education/training programs exist in almost all jurisdictions around the world. They are generally accepted as an efficient and effective means for learning to drive, and, more importantly, for learning to drive safely, although empirical evidence for safety benefits is lacking. Recently, there has been a heightened interest in driver education/training, largely as a result of the adoption of graduated licensing in a few jurisdictions in North America and elsewhere. These jurisdictions have effectively elevated the status of driver education/training by integrating it into the licensing system. Implicitly, this suggests that driver education provides safety benefits. This article provides a contemporary review of the value of driver education/training, particularly in relation to new licensing systems such as graduated ones. The article examines the safety benefits of driver education/training and considers the merits of integrating driver education/training programs with new approaches to the licensing of young drivers.

Accidents, Traffic↗
PubMed2004

Graduated driver licensing for reducing motor vehicle crashes among young drivers.

BACKGROUND: Graduated driver licensing (GDL) has been proposed as a means of reducing crash rates among novice drivers by gradually introducing them to higher risk driving situations. OBJECTIVES: To examine the effectiveness of GDL systems in reducing crash rates of young drivers. SEARCH STRATEGY: Studies were identified through searches of MEDLINE, EMBASE, CINAHL, Healthstar, Web of Science, NTIS Bibliographic Database, TRIS Online, SIGLE, the World Wide Web, relevant conference proceedings, consultation with experts and authors, and reference lists. The search was not restricted by language or publication status. SELECTION CRITERIA: Studies were included if: 1) they compared outcomes pre- and post-implementation of a GDL program within the same jurisdiction, 2) comparisons were made between jurisdictions with and without GDL, or 3) both. Studies had to report at least one objective, quantified outcome. Two reviewers independently screened searches and assessed the full text of potentially relevant studies for inclusion using a standard form. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and checked by a second. Additional data were requested from authors. Results were not pooled due to substantial heterogeneity between studies. Percentage change was calculated for each year after the intervention, using one year prior to the intervention as the baseline rate. Results were adjusted by internal controls. Analyses were stratified by different denominators (population, licensed drivers). Results were calculated for the different crash types (overall, injury, fatal, night-time, alcohol, and those resulting in hospitalization). Results were presented for 16 year-olds alone and all teenage drivers combined. MAIN RESULTS: We included 13 studies evaluating 12 GDL programs that were implemented between 1979 and 1998 in the US (n=7), Canada (3), New Zealand (1), and Australia (1). Programs varied in their restrictions during the intermediate stage: e.g. night curfews (8); limitations of extra passengers (2); roadway restrictions (1). Based on the Insurance Institute for Highway Safety classification scheme, no programs were good, six were acceptable, five were marginal, and one was poor. Reductions in crash rates were seen in all jurisdictions and for all crash types. Among 16 year-old drivers, the median decrease in per population overall crash rates during the first year was 31% (range 26-41%). Per population injury crash rates were similar (median 28%, range 4-43%). Results for all teenage drivers, rates per licensed driver, and rates adjusting for internal controls were generally reduced when comparing within jurisdictions. REVIEWERS' CONCLUSIONS: The existing evidence shows that GDL is effective in reducing the crash rates of young drivers, although the magnitude of the effect is unclear. The conclusions are supported by consistent direction of the findings, and the temporal relationship and plausibility of the association. The reviewers have made recommendations for primary research on GDL (e.g. study methods, standardized reporting of outcomes and results, long-term follow-up). The project has also shown what is needed to carry out systematic reviews of observational studies (e.g. quality assessment instruments).

Accidents, Traffic↗
PubMed1999

Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus.

The emergence in vaccinated individuals of hepatitis B virus (HBV) mutants with amino acid substitutions within the a determinant of the surface protein has raised the possibility that such variants represent neutralization escape mutants. We previously demonstrated that one such mutant HBV, strain AS, with an arginine substituted for glycine at surface gene codon 145, was infectious and pathogenic in seronegative chimpanzees. In the present study, the protective efficacy of licensed hepatitis B vaccines was evaluated against challenge with this mutant virus. Four chimpanzees were immunized with 1 of 2 licensed recombinant hepatitis B vaccines. Shortly after the chimpanzees developed antibodies to hepatitis B surface antigen (anti-HBs), they were challenged intravenously with mutant HBV strain AS. Two unvaccinated chimpanzees served as positive controls. The 4 vaccinated chimpanzees did not develop evidence of HBV infection or hepatitis during 2 years following virus challenge. In contrast, the 2 unvaccinated chimpanzees developed HBV infection and hepatitis. Serum anti-HBs in the vaccinated chimpanzees reacted not only with wild-type surface antigen, but also with mutant surface antigen by competition enzyme-linked immunosorbent assay (ELISA). Thus, immunization of chimpanzees with licensed recombinant hepatitis B vaccines stimulates anti-HBs that is broadly reactive and affords protection against infection with a surface gene mutant of HBV, suggesting that properly immunized individuals are not at significant risk of infection with this prototype variant strain of HBV.

Animals↗
PubMed2005

DNA replication licensing in peripheral B-cell lymphoma.

Peripheral B-cell lymphomas representing 90% of lymphoid neoplasms are divided into low- and high-growth fraction lymphomas. Here we investigate regulation of DNA replication licensing during B-cell lymphomagenesis. Combined analysis of origin licensing factors Mcm2 and geminin with the proliferation marker Ki67 in SLL/CLL, MCL, DLBCL and Burkitt lymphoma reveals for the first time the precise cell cycle state of these entities. Given that tight Mcm2 downregulation defines the quiescent state (G0) and that both high- and low-growth fraction lymphomas express Mcm2, the data demonstrate that neoplastic lymphocytes of SLL/CLL and MCL reside in an "in-cycle" G1 state and not in G0 as previously thought. Absence of the S/G2/M phase marker geminin in SLL/CLL and MCL further indicates failure of cell cycle progression in these tumours. In contrast, the high-growth fraction lymphomas DLBCL and Burkitt lymphoma exhibit differential expression of geminin, with the geminin/Ki67 ratio increasing for more aggressive neoplasms in keeping with a shortened G1 phase and thus representing an important discriminator for differential diagnosis. These data provide new insights into abrogation of cell cycle control during B cell lymphomagenesis and suggest that combined analysis of origin licensing factors may contribute to improved treatment decisions and prognosis in haematopoietic malignancies.

Biomarkers, Tumor↗
PubMed2002

Medicines for children licensed by the European Agency for the Evaluation of Medicinal Products.

OBJECTIVE: . The aim of this study was to evaluate the number and the characteristics of medicines approved for children in Europe by the European Agency for the Evaluation of Medicinal Products (EMEA) and whether the paediatric studies supporting the authorisation were in accordance with the Note for Guidance on the Clinical Investigation of Medicinal Products in children (CPMP/ICH/2711/99). We also considered any possible difference between the EMEA and the Food and Drug Administration (FDA) paediatric medicines evaluations. METHODS: . We examined the drugs authorised by the EMEA through the centralised procedure from January 1995 to September 2001 deriving information from the "European Medicines - Database" (EMD) set up in 1998 by the Italian Group for Pharmacoeconomic Studies (GISF) and sponsored by the Italian Ministry of Health. The analysis of paediatric data has been managed by experts belonging to the Clinical Pharmacology Working Group of the Italian Paediatric Society. The following parameters were assessed: active substance, year of approval, anatomical therapeutic and chemical (ATC) code, therapeutic indications, age for which the drug is authorised, interest to children and paediatric studies supporting a paediatric authorisation. European Public Assessment Reports (EPARs) were considered as reference sources. RESULTS: . The median percentage of drugs authorised for children from 1995 to 2001 (September) is 35% of the total of commercially available drugs; only 16 medicines have been approved for children under 2 years of age (11%), ten of these being vaccines. Medicines for children shared out 9 ATC classes, 24 belonging to the J- (anti-infective agents) -ATC class. Thirty-nine medicines were authorised on the basis of at least one clinical trial (27 phase III, 6 phase II, 6 phase I) while eight active substances have been licensed without any paediatric investigation. CONCLUSIONS: . Under the EMEA centralised procedure, several active substances have been licensed for children. Consequently serious and life-threatening diseases as AIDS and diabetes are now treatable, in a legal framework overcoming the orphan status of the past years. Despite the reported encouraging results, the number of drugs devoted to children remain low and important ATC classes, as L-(oncology) or N-(neurology), are still 'orphans' of innovative medicines. At the same time few medicinal products are specifically studied in children. Consequently, more efforts have to be made to increase the number of drugs assessed and licensed for the paediatric population, and manufacturers should be required to supply data on the effects of new drugs in children when the products are expected to offer a benefit over existing therapies.

Adolescent↗
PubMed2006

Subtypes of oligodendroglioma defined by 1p,19q deletions, differ in the proportion of apoptotic cells but not in replication-licensed non-proliferating cells.

Oligodendrogliomas may be divided into those with deletion of chromosomes 1p and 19q (Del+), and those without (Del-). Del+ tumours show better survival and chemoresponsiveness but the reason for this difference is unknown. We have investigated whether these subgroups differ in (a) apoptotic index, (b) the proportion of cells licensed for DNA replication but not in-cycle, and (c) the relative length of G1-phase. Fluorescence in situ hybridisation with probes to 1p and 19q was used to determine the deletion status of 54 oligodendrogliomas, including WHO grades II and III. The apoptotic index was determined using counts of apoptotic bodies. Replication-licensed non-proliferating cells were determined from the Mcm2 minus Ki67 labelling index, whilst the geminin to Ki67 ratio was used as a measure of the relative length of G1. Del+ oligodendrogliomas showed a higher apoptotic index than Del- tumours (P=0.037); this was not accounted for by differences in tumour grade or in proliferation. There were no differences in the Mcm2-Ki67 index or in the geminin/Ki67 ratio between the subgroups, but grade III tumours showed a higher proportion of licensed non-proliferating cells than grade II tumours (P=0.001). An increased susceptibility to apoptosis in oligodendrogliomas with 1p+/-19q deletion may be important in their improved clinical outcome compared to Del- tumours.

Adult↗
PubMed2006

Suicide by shooting is correlated to rate of gun licenses in Austrian counties.

OBJECTIVES: Shooting as method of suicide has increased considerably in Austria over recent decades and represented 23.5% of all suicides among men during the period 1990-2000. It is thought that the availability of guns could lead to their use in acts of suicide, and therefore we investigated the numbers of gun licenses (which constitutes ownership of guns and permission to carry a gun) in the nine Austrian counties and their correlation with suicides by shooting and other methods. METHODS: We studied registered suicides, including the method used, between 1990 and 2000 in Austria and the numbers of gun licenses held in the nine counties of Austria in the same period. RESULTS: We found a strong correlation between the average gun license rate for the period 1990-2000 and suicides by shooting (r = 0.967), and only very weak correlation, and for some of the years under investigation a negative correlation, with other methods of committing suicide (r = 0.117) and the suicide rate in general (r = 0.383). CONCLUSIONS: As shooting as a method of suicide has increased in Austria in recent decades, and is a highly lethal method, the finding that the shooting suicide rate is related to the extent of gun ownership deserves attention, especially as there is evidence that restriction of gun ownership is an important factor in suicide prevention.

Austria↗
PubMed1988

Effects of license revocation on drunk-driving offenders.

Revoking or suspending the licenses of persons convicted of driving while intoxicated has often been claimed to be uniquely effective in reducing subsequent dangerous driving, as indexed by crashes and violations. This finding holds despite the impression that many suspended and revoked drivers continue to drive illegally. The research described here inquires into the operation of license actions. It uses intensive personal interviews with offenders to obtain information concerning the nature and amount of illegal driving and the effects of license deprivation on employment and other aspects of the offenders' lives.

Accidents, Traffic↗