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PubMed2005

Licensing of natural killer cells by host major histocompatibility complex class I molecules.

Self versus non-self discrimination is a central theme in biology from plants to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through 'licensing' by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells--licensed or unlicensed--and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.

Animals↗

PubMed2004

DNA replication licensing and cell cycle kinetics of oligodendroglial tumours.

The convergence point of growth-signalling pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes (pre-RCs), resulting in chromatin being 'licensed' for DNA replication in the subsequent S phase. The Mcm2-7 complex is a core constituent of the pre-RC, whose recruitment to replication origins is dependent on the Cdt1 loading factor. Geminin is a potent inhibitor of the initiation of DNA replication by preventing Mcm2-7 assembly at origins via its interaction with Cdt1, ensuring genomic integrity through suppression of re-initiation events in S phase. Here we investigate the regulation of Ki67, Mcm2, p21, caspase 3 and Geminin in a series of 55 oligodendrogliomas to provide an integrated picture of how cellular proliferation and programmed cell death are dysregulated in these tumours. Geminin does not behave as an inhibitor of cell proliferation, its labelling index rising with increasing growth fraction as defined by Ki67 or Mcm2 expression. Geminin is expressed in a higher proportion of cells in higher grade tumours (P<0.001) and shows a strong correlation to proliferation and replication licensing (P<0.01), but not apoptosis. Increasing tumour anaplasia is not associated with loss of Geminin. Importantly, the G1 phase of the proliferative cell cycle, as assessed by the Geminin/Ki67 ratio, shortens with increasing anaplasia, providing new potential algorithms for prognostic assessment. Origin licensing proteins thus provide powerful novel tools for assessment of tumour cell cycle kinetics in routinely processed surgical biopsy material.

Adult↗

PubMed2003

Human cytomegalovirus prevents replication licensing by inhibiting MCM loading onto chromatin.

To allow DNA replication only once per cell cycle, origins of replication are reactivated ('licensed') during each G1 phase. Licensing is facilitated by assembly of the pre-replicative complex (pre-RC) at origins that concludes with loading the mini-chromosome maintenance (MCM) complex onto chromatin. Here we show that a virus exploits pre-RC assembly to selectively inhibit cellular DNA replication. Infection of quiescent primary fibroblasts with human cytomegalovirus (HCMV) induces all pre-RC factors. Although this is sufficient to assemble the MCM-loading factors onto chromatin, as it is in serum-stimulated cells, the virus inhibits loading of the MCM complex itself, thereby prematurely abrogating replication licensing. This provides a new level of control in pre-RC assembly and a mechanistic rationale for the unusual HCMV-induced G1 arrest that occurs despite the activation of the cyclin E-dependent transcription programme. Thus, this particularly large virus might thereby secure the supply with essential replication factors but omit competitive cellular DNA replication.

Animals↗

PubMed1991

Effects of restrictive licensing of handguns on homicide and suicide in the District of Columbia.

BACKGROUND: Whether restricting access to handguns will reduce firearm-related homicides and suicides is currently a matter of intense debate. In 1976 the District of Columbia adopted a law that banned the purchase, sale, transfer, or possession of handguns by civilians. We evaluated the effect of implementing this law on the frequency of homicides and suicides. METHODS: Homicides and suicides committed from 1968 through 1987 were classified according to place of occurrence (within the District of Columbia or in adjacent metropolitan areas where the law did not apply), cause (homicide or suicide), mechanism of death (firearms or other means), and time of occurrence (before or after the implementation of the law). The number of suicides and homicides was calculated for each month during the study period, and differences between the mean monthly totals before and after the law went into effect were estimated. RESULTS: In Washington, D.C., the adoption of the gun-licensing law coincided with an abrupt decline in homicides by firearms (a reduction of 3.3 per month, or 25 percent) and suicides by firearms (reduction, 0.6 per month, or 23 percent). No similar reductions were observed in the number of homicides or suicides committed by other means, nor were there similar reductions in the adjacent metropolitan areas in Maryland and Virginia. There were also no increases in homicides or suicides by other methods, as would be expected if equally lethal means were substituted for handguns. CONCLUSIONS: Restrictive licensing of handguns was associated with a prompt decline in homicides and suicides by firearms in the District of Columbia. No such decline was observed for homicides or suicides in which guns were not used, and no decline was seen in adjacent metropolitan areas where restrictive licensing did not apply. Our data suggest that restrictions on access to guns in the District of Columbia prevented an average of 47 deaths each year after the law was implemented.

Cause of Death↗

PubMed2004

Blood pressure and heart rate of students undergoing a medical licensing examination.

AIMS: To assess the effect of a real life mental stress situation on blood pressure (BP) and heart rate (HR) in students undergoing a medical licensing examination. METHOD: Prospective observational study of 121 medical students taking the final licensing exam. BP and HR were taken before and after the exam. Additionally, BP was measured by ambulatory BP monitoring device and HR was recorded continuously by an HR monitor belt in 25 students throughout the examination. MAJOR FINDINGS: Diastolic BP (DBP) increased from 81 +/- 10 mmHg before the exam to 86 +/- 9 mmHg (p = 0.008) during the exam and to 88 +/- 11 mmHg, (p = 0.007) 15 min after the exam. Systolic BP (SBP) did not increase significantly during (from 131 +/- 14 before the exam to 136 +/- 18 mmHg) and after the exam (135 +/- 16 mmHg). HR decreased during (to 100 +/- 18 beats/min, p < 0.001), and after the exam (to 95 +/- 19 beats/min, p < 0.001) compared to values before the exam (114 +/- 19 beats/min). SBP was higher in male students compared to female students before (138 +/- 10 vs 125 +/- 18 mmHg) and after (126 +/- 18 vs 115 +/- 17 mmHg) the exam (p < 0.01). CONCLUSION: Only DBP increased during medical licensing examination, albeit within a small range. SBP did not change significantly and HR decreased during the exam. Male students showed a higher SBP compared to female students.

Adrenergic beta-Antagonists↗

PubMed1993

Reversible effects of nuclear membrane permeabilization on DNA replication: evidence for a positive licensing factor.

We have investigated the mechanism which prevents reinitiation of DNA replication within a single cell cycle by exploiting the observation that intact G2 HeLa nuclei do not replicate in Xenopus egg extract, unless their nuclear membranes are first permeabilized (Leno et al., 1992). We have asked if nuclear membrane permeabilization allows escape of a negative inhibitor from the replicated nucleus or entry of a positive activator as proposed in the licensing factor hypothesis of Blow and Laskey (1988). We have distinguished these possibilities by repairing permeabilized nuclear membranes after allowing soluble factors to escape. Membrane repair of G2 nuclei reverses the effects of permeabilization arguing that escape of diffusible inhibitors is not sufficient to allow replication, but that entry of diffusible activators is required. Membrane repair has no significant effect on G1 nuclei. Pre-incubation of permeable G2 nuclei in the soluble fraction of egg extract before membrane repair allows semiconservative DNA replication of these nuclei when incubated in complete extract. Addition of the same fraction after membrane repair has no effect. Our results provide direct evidence for a positively acting "licensing" activity which is excluded form the interphase nucleus by the nuclear membrane. Nuclear membrane permeabilization and repair can be used as an assay for licensing activity which could lead to its purification and subsequent analysis of its action within the nucleus.

Animals↗

PubMed1995

An analysis of the regulation of DNA synthesis by cdk2, Cip1, and licensing factor.

The activation of DNA replication appears to involve at least four steps. These include origin recognition, origin unwinding, primer synthesis, and a switching step to a continuous elongation mode. Moreover, in higher eukaryotes a number of studies have shown that much of the DNA replication which occurs is restricted to specific sites within the nuclei. It has been proposed that these replication foci are composed of a large number of origin sites which are clustered together into an aggregate. The molecular basis for this aggregation is currently not well understood. Regulation of the activation of DNA replication is a complicated process. The G1-S kinase cdk2 is a positive regulator of replication. The p21 protein is a negative regulator of replication both by inhibiting cdk2 kinase and the replication protein PCNA. Moreover, it has been proposed that origin usage is restricted to a single firing per cell cycle by a "licensing factor." Using a cell-free replication system derived from Xenopus eggs we have investigated at what step in the replication process these regulators participate. We present evidence that the clustered organization of DNA into foci is not a transient arrangement, but rather, it persists following DNA replication. We also find that foci form on both sperm chromatin and bacteriophage lambda DNA incubated in extracts depleted of cdk2 kinase. Therefore, our data support the conclusion that organization of chromatin into foci is an early event in the replication pathway preceding activation of cdk2 kinase. With respect to the role of cdk2 during activation of DNA replication we find that in cdk2-depleted extracts primer synthesis does not occur and RP-A remains tightly associated with foci. This strongly suggests that cdk2 kinase is required for activating the origin unwinding step of the replication process. Consistent with this interpretation we find that addition of rate limiting quantities of the cdk2 inhibitor p21 protein to an extract delays primer synthesis. Interestingly, in the presence of p21 primer synthesis does occur after a delay and then replication arrests. This is consistent with the published demonstration that p21 can inhibit PCNA, a protein required for replication beyond the priming step. Therefore, our results provide additional support to the proposal that the post-priming switching step is a key regulatory step in replication. With respect to the role of licensing factor during DNA replication it has recently been shown that treatment of mitotic extracts with kinase inhibitor DMAP inactivates "licensing factor."(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1997

Licensing of DNA replication by a multi-protein complex of MCM/P1 proteins in Xenopus eggs.

In eukaryotes, chromosomal DNA is licensed for a single round of replication in each cell cycle. Xenopus MCM3 protein has been implicated in the licensing of replication in egg extract. We have cloned cDNAs encoding five immunologically distinct proteins associated with Xenopus MCM3 as members of the MCM/P1 family. Six Xenopus MCM proteins formed a physical complex in the egg extract, bound to unreplicated chromatin before the formation of nuclei, and apparently displaced from replicated chromatin. The requirement of six XMCM proteins for the replication activity of the egg extract before nuclear formation suggests that their re-association with replicated chromatin at the end of the mitotic cell cycle is a key step for the licensing of replication.

Adenosine Triphosphatases↗

PubMed1998

Sharing genetic origins information in donor assisted conception: views from licensed centres on HFEA donor information form (91) 4.

Section 31 of the Human Fertilization and Embryology Act 1990 permits people born as a result of licensed treatments provided in the UK to seek certain information about their genetic origins held on the Human Fertilization and Embryology Authority (HFEA) Register of Information. The precise nature of such information is to be specified in Regulations that have yet to be determined by the Secretary of State. The Register comprises data submitted to the Authority by licensed centres on HFEA Donor Information Form (91) 4. This paper reports on a survey of views of licensed centres concerning the adequacy of this form and centres' experiences of gathering information from donors. The survey shows that centres' experiences vary considerably, and the authors argue that there is a case for the sharing of centres' experiences and dissemination of effective strategies. The paper further discusses the nature of information that might become available to individuals seeking information from the HFEA. While requests for non-identifying information concerning the donor cannot be made prior to 2010, any information made available then is inevitably dependent on current practice in centres. The authors conclude that current variability in practice does not best serve the interests of donor offspring who may seek information about their genetic origins.

Attitude↗

PubMed1997

Medical assessment for licensing of taxi drivers by Scottish local authorities.

In the UK, licensing of taxi drivers is dealt with by local government authorities. In Scotland, before the recent reorganization of local government, taxi licensing was under the jurisdiction of District Councils, so a telephone survey was conducted of all 52 mainland Scottish District Councils to ascertain the procedures which were being employed in assessing medical fitness to drive a taxi, for which there is no national standard. Medical enquiries relevant to fitness to drive were being made by 41 (79%) of local authorities, but in 38 (73%) this was limited to a single question about health. No enquiry regarding health status was being made by 11 (21%) District Councils (all serving < 100,000 population size). Only three Scottish District Councils conducted a routine medical examination of all applicants. Thirteen of the 15 large (> 100,000 population size), and 20 of the 21 medium-sized (50,000-100,000) Scottish District Councils carried out medical examinations either when a relevant medical disorder was declared by the applicant, or when the applicant was above a defined age (which varied between local authorities). The small local authorities (population < 50,000) examined only those applicants who declared medical disorders. This survey has shown considerable variation and limitations in the approach of the previously existing Scottish District Councils to the assessment of medical fitness to drive of applicants for taxi licences. It is suggested that national standards and guidelines are required for medical fitness to drive in relation to taxi licensing.

Automobile Driving↗

PubMed1988

Prediction of licensing examination scores in physical therapy graduates.

The primary purpose of this study was to determine which information available on applicants to the University of New Mexico physical therapy program would best predict performance on the licensing examination. The secondary purpose was to provide documentation of a procedure for selection that could be useful to other programs in other settings. American College Testing (ACT) scores, prerequisite and nonprerequisite grade point averages (GPAs), and interview and recommendation scores were used to predict licensing examination scores for the classes graduating from 1980 to 1984. Six of the regression analyses were significant, but three had similar correlations that were much higher than the rest. The variables in those three regression analyses were ACT composite score and both GPAs; ACT composite score, both GPAs, and interview score; and ACT composite score, prerequisite GPA, and interview score. The results of this study suggest that selection committees use standardized ability tests as admission criteria because the ACT scores accounted for the most variance in licensing examination scores. Other professional schools might also benefit by applying the procedures used in this study to their own data to develop prediction equations.

Educational Measurement↗

PubMed1998

Potential human and economic cost-savings attributable to vision testing policies for driver license renewal, 1989-1991.

PURPOSE: This study assessed the impact of vision-related relicensing policies on traffic fatalities in the United States. There is a limited empirical basis for state vision testing policies for relicensing. Furthermore, it is uncertain whether contemporary vision standards for driver licensing achieve their implicit goal of protecting the public's health, or inappropriately restrict the mobility of competent drivers. METHODS: The 48 contiguous states and the District of Columbia were the "subjects" in this investigation. During the study period (1989 to 1991), 10 states did not require vision testing for driver license renewal. Multiple regression modeling was used to assess the impact of vision-related relicensing policies on traffic safety and to estimate the number of avoidable vehicle occupant fatalities and corresponding economic costs associated with traffic crashes involving older drivers (> or = 60 years). The primary data source for this investigation was the Fatal Accident Reporting System (FARS) database. RESULTS: Vision-related relicensing policies were significantly associated (p < 0.05) with lower vehicle occupant fatality rates of older drivers. According to the final regression model, approximately 222 fewer vehicle occupant fatalities (-12.2%) associated with older drivers would be expected for the 3-year period if mandatory vision testing policies had been in effect in 8 of the 10 states without such policies. Conservatively, those avoidable deaths represent an estimated $31 million in avoidable economic costs. CONCLUSIONS: State-level mandatory vision testing for relicensure may enhance traffic safety and reduce the economic burden of fatal crashes. Vision testing requirements should be maintained by jurisdictions with such requirements, and jurisdictions without such requirements should consider the potential traffic safety benefits of vision testing for driver license renewal.

Accidents, Traffic↗

PubMed1996

Licensing, quality of care and the surveillance process.

As part of the evaluation of an experimental programme of surveillance of institutions for the semi-independent and frail elderly using the regulation, assessment, follow-up (RAF) method, an examination was made of the licensing status, quality of care, and completeness of the surveillance process. Included in the examination were 126 institutions which underwent the surveillance process between 1990 and 1993. Aims to investigate whether the RAF method of surveillance was being implemented in a professional and uniform manner. Concludes that surveyor's recommendations to grant or not grant a licence were usually based on findings about the quality of care. Nevertheless, in order to reinforce the relationship between licensing and quality of care, it was suggested that surveyors be given clear criteria of quality on which to base their recommendations regarding conditional licensing. It was found that the surveillance process is indeed implemented uniformly in long-term care institutions of varying quality.

Accreditation↗

PubMed2005

Alcohol price elasticities in control and license states in the United States, 1982-99.

AIM: The demand for alcohol has been demonstrated repeatedly to be sensitive to price changes. However, estimated price elasticities vary by study region and over time. One explanation for these variations might be that different countries or parts of countries have had different alcohol control systems. The hypothesis addressed in this study was that a regulated market leads to higher transaction costs associated with purchasing alcohol, which in turn increases the full price of the beverages (the nominal cash price plus transaction costs). As a result, the cash price of alcohol represents a smaller part of the full price in a highly regulated market. Assuming that customers respond primarily to changes in full price, the demand for alcohol should be less sensitive to changes in cash price where regulation is stricter. This study examined whether variations in price elasticities were a function of the different regulatory systems in control and license states in the United States during the period 1982-99. DATA AND METHODS: Time-series cross-sectional analyses (in 50 states over 18 years) were conducted. Elasticities were estimated using a multiplicative model based upon first-differences of time-series within states. Disposable income and other socio-demographic variables were used as control variables. All data were obtained from archival sources. FINDINGS: The demand for spirits and beer were significantly more sensitive to price changes in license states than in control states. The estimated price elasticity for wine sales was also somewhat larger in license states, but not significantly so. CONCLUSION: The lower price elasticities for spirits and beer in the control states support the hypothesis that customers respond primarily to changes in the full price of alcohol.

Alcohol Drinking↗

PubMed1991

Discussion on the 'problem of driving license for people with epilepsy'.

From the socio-medical points of view, the problem of a driving license for people with epilepsy was discussed. It was concluded that not only seizure but also the presence of side-effects of drugs and of personality change should be assessed to allow them the license. Finally, a medical guideline was proposed for the driving license for people with epilepsy.

Anticonvulsants↗

PubMed2002

Environmental tobacco smoke in homes, motor vehicles and licensed premises: community attitudes and practices.

OBJECTIVE: To assess community knowledge, attitudes and practices in relation to environmental tobacco smoke (ETS) especially in homes, private motor vehicles and licensed premises, and to document levels of support for further government legislation. METHODS: 656 persons aged 18 years and over, a sub-sample in a computer-assisted telephone survey of 2,087 randomly selected respondents across NSW, answered 12 ETS-specific questions. The whole sample was asked demographic, smoking status and household membership questions. The overall response rate was 61.4% (consent rate 75.4%). RESULTS: Overall, 32.8% (95% CI 27.8-37.8) of children aged 0-4 years in the households surveyed were reported to live with at least one smoker. Agreement about ETS hazards was lowest in relation to child ear problems (31.2%) and sudden infant death syndrome (50.6%). Complete bans on smoking were reported in 69.9% of homes and 77.1% of private motor vehicles. The percentages favouring total bans in homes (p < 0.001) and private motor vehicles (p < 0.001) were significantly lower among smokers than non-smokers. Overall, 55.8% supported legislation to ban smoking in private vehicles carrying children. The majority support restrictions on smoking in non-eating areas of licensed clubs (88.7%) and hotels (84.8%). Overall, the data indicate a ban on smoking in licensed premises is likely to increase business. CONCLUSION: Smoking is banned in most NSW homes and private motor vehicles. Acceptance of ETS risks is high but there are important knowledge gaps. Considerable support exists for further government regulation of ETS. Media campaigns are likely to reinforce a public environment already receptive of the need for more government ETS restrictions.

Adolescent↗

PubMed1987

Probabilistic reliability analysis, quantitative safety goals, and nuclear licensing in the United Kingdom.

Although unpublicized, the use of quantitative safety goals and probabilistic reliability analysis for licensing nuclear reactors has become a reality in the United Kingdom. This conclusion results from an examination of the process leading to the licensing of the Sizewell B PWR in England. The licensing process for this reactor has substantial implications for nuclear safety standards in Britain, and is examined in the context of the growing trend towards quantitative safety goals in the United States.

Accident Prevention↗

PubMed1995

Aboriginal wellbeing and liquor licensing legislation in Western Australia.

This paper is based on the results of a project undertaken as the basis for a submission to the committee established to review the Western Australian Liquor Licensing Act 1988. It reports on key issues relating to liquor licensing, as identified by members of regional Aboriginal organisations. Among these issues are the promotion of alcohol consumption and misuse, discriminatory practices by licensees and the police and the need for greater community involvement in liquor licensing decisions. To address these issues, members of the participating organisations proposed: inclusion of a harm-minimisation objective in the Act, education and training programs for the public, licensees and the police, and industry funding for harm-minimisation programs.

Alcohol Drinking↗