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PubMed2003

(Q)SARs: gatekeepers against risk on chemicals?

ECOSAR and DEREKfW predictions for the (eco)toxicological effects of circa 70 substances were compared with experimental data for risk assessment purposes. These and other (quantitative) structure-activity relationships ((Q)SARs) programs will play an important role in future chemical policies, such as in the European Union and The Netherlands, to reduce animal testing and costs and to speed up the number of risk assessments for hazardous chemicals. The two programs, ECOSAR and DEREKfW, were selected because they are easy to use and transparent in their predictions. They predict to which chemical class a substance belongs and also predict some (eco)toxicological properties. ECOSAR categorised 87% of the chemicals correctly in chemical classes. With regard to predicting ecotoxicity, criteria were drawn up for the reliability of the QSARs provided by ECOSAR. Application of these criteria had the result that half of the regression lines from ECOSAR were considered unreliable beforehand. It turned out, however, that the "unreliable" regression lines predicted similar accurately as the "reliable" lines, although much less chemicals were available for validating the "unreliable" QSARs. The overall accurate prediction of toxicity by ECOSAR was 67%. DEREKfW categorised 90% of the chemicals correctly in chemical classes, while 10% of the structural fragments needed a more detailed description. The accuracy of prediction was around 60% for sensitisation, 75% for genotoxicity and carcinogenicity for a limited number of chemicals. Irritation and reproductive toxicity were predicted poorly. Finally, it should be stressed that regulators and industries need to agree on the acceptability criteria relating to false negative and false positive (Q)SAR predictions. This to prevent unnecessary animal testing when regulators do not sufficiently rely on (Q)SAR predictions or to prevent too much faith in (Q)SAR predictions which will then may cause an insufficient protection of man and the environment. Therefore, if the regulatory trend is that (Q)SARs have to be applied more and more systematically in the risk assessment process, their validity and the available tools have to be explored further.

Computer Simulation↗
PubMed2003

Traffic control: p120-catenin acts as a gatekeeper to control the fate of classical cadherins in mammalian cells.

Proteins of the p120 family have been implicated in the regulation of cadherin-based cell adhesion, but their relative importance in this process and their mechanism of action have remained less clear. Three papers in this issue suggest that p120 plays a key role in maintaining normal levels of cadherin in mammalian cells, and that it may do so by regulating cadherin trafficking (Chen et al., 2003; Davis et al., 2003; Xiao et al., 2003).

Adherens Junctions↗
PubMed2005

LSP1 is an endothelial gatekeeper of leukocyte transendothelial migration.

Leukocyte-specific protein 1 (LSP1), an F-actin binding protein and a major downstream substrate of p38 mitogen-activated protein kinase as well as protein kinase C, has been reported to be important in leukocyte chemotaxis. Although its distribution has been thought to be restricted to leukocytes, herein we report that LSP1 is expressed in endothelium and is essential to permit neutrophil emigration. Using intravital microscopy to directly visualize leukocyte rolling, adhesion, and emigration in postcapillary venules in LSP1-deficient (Lsp1-/-) mice, we found that LSP1 deficiency inhibits neutrophil extravasation in response to various cytokines (tumor necrosis factor-alpha and interleukin-1beta) and to neutrophil chemokine keratinocyte-derived chemokine in vivo. LSP1 deficiency did not affect leukocyte rolling or adhesion. Generation of Lsp1-/- chimeric mice using bone marrow transplantation revealed that in mice with Lsp1-/- endothelial cells and wild-type leukocytes, neutrophil transendothelial migration out of postcapillary venules is markedly restricted. In contrast, Lsp1-/- neutrophils in wild-type mice were able to extravasate normally. Consistent with altered endothelial function was a reduction in vascular permeability to histamine in Lsp1-/- animals. Western blot analysis and immunofluorescence microscopy examination confirmed the presence of LSP1 in wild-type but not in Lsp1-/- mouse microvascular endothelial cells. Cultured human endothelial cells also stained positive for LSP1. Our results suggest that LSP1 expressed in endothelium regulates neutrophil transendothelial migration.

Animals↗
PubMed2003

Structure of a viral DNA gatekeeper at 10 A resolution by cryo-electron microscopy.

In tailed bacteriophages and herpes viruses, the viral DNA is packaged through the portal protein channel. Channel closure is essential to prevent DNA release after packaging. Here we present the connector structure from bacteriophage SPP1 using cryo-electron microscopy and single particle analysis. The multiprotein complex comprises the portal protein gp6 and the head completion proteins gp15 and gp16. Although we show that gp6 in the connector has a fold similar to that of the isolated portal protein, we observe conformational changes in the region of gp6 exposed to the DNA-packaging ATPase and to gp15. This reorganization does not cause closure of the channel. The connector channel traverses the full height of gp6 and gp15, but it is closed by gp16 at the bottom of the complex. Gp16 acts as a valve whose closure prevents DNA leakage, while its opening is required for DNA release upon interaction of the virus with its host.

Adenosine Triphosphatases↗
PubMed1996

The journey of incontinent women from community to university clinic; implications for selection bias, gatekeeper function, and primary care.

BACKGROUND: The selection process of patients from community to hospitals may introduce bias into research and hamper the generalization of hospital-based research back to general practice. OBJECTIVE: The objective of this study was to use female urinary incontinence as a model in an attempt to provide empirical support for selection bias. METHOD: The analyses are based on three populations of incontinent women: community level (epidemiological survey, 535 women), primary care level (general practice, prospective clinical study, 105 women), and secondary care level (university hospital, prospective clinical study, 228 women). RESULTS: The general practice patients were older and the hospital patients younger than those in the community. From community via general practice to hospital, there was an increase in duration, frequency of leakage, amount of leakage, severity and perceived impact of incontinence. Help-seeking at the primary care level was associated with increasing age and severity, and with urge symptoms and substantial impact. Referral from general practice to hospital level was only associated with age and urge symptoms. CONCLUSION: The study provides empirical evidence to support the existence of selection bias. This phenomenon must not be overlooked when recommendations developed at the consultant level are presented at a level with a significantly different clinical picture of a condition.

Adult↗
PubMed2002

Microarrayed allergen molecules: diagnostic gatekeepers for allergy treatment.

Type I allergy is an immunoglobulin E (IgE)-mediated hypersensitivity disease affecting more than 25% of the population. Currently, diagnosis of allergy is performed by provocation testing and IgE serology using allergen extracts. This process defines allergen-containing sources but cannot identify the disease-eliciting allergenic molecules. We have applied microarray technology to develop a miniaturized allergy test containing 94 purified allergen molecules that represent the most common allergen sources. The allergen microarray allows the determination and monitoring of allergic patients' IgE reactivity profiles to large numbers of disease-causing allergens by using single measurements and minute amounts of serum. This method may change established practice in allergy diagnosis, prevention, and therapy. In addition, microarrayed antigens may be applied to the diagnosis of autoimmune and infectious diseases.

Allergens↗
PubMed1990

Help for the gatekeepers: comment and summation on the admission process.

The author comments on articles that discuss the roles of demographic variables, qualitative variables, and the interview in making sound selection for medical school admission; analyze the effectiveness of traditional predictors in selecting successful students; and examine the predictors that best identify minority students likely to succeed in medical training. Together, the articles review the literature, analyze the findings, and recommend sound practices and areas of future research germane to selecting students. The discussions highlight the predictor role, initial importance, and relatively short half-life of academic criteria in physicians' total careers, and emphasize that academic predictors must be complemented by other factors in the applicant's background. Because selection for medical school leads in almost all cases to eventual practice as a physician, the admission decision has far-reaching impact. Those concerned with the admission process should use the distilled information in these articles to improve the assessment of applicants and the selection process.

Achievement↗
PubMed1990

The pediatrician as gatekeeper to mental health care for children: do parents' concerns open the gate?

Data from a study of children seen for pediatric care in a Health Maintenance Organization are used to examine factors which influence the likelihood that a pediatrician will identify a psychiatric problem and refer an identified child to a mental health specialist for further evaluation and treatment. Parental level of distress, family psychiatric history, and discussion of parental concerns with the pediatrician were found to be important. Characteristics of the service delivery system which may impede appropriate identification and referral are discussed. Implications for participation of child and adolescent psychiatrists in the training of pediatricians are presented.

Child↗
PubMed1984

The physician as gatekeeper. Determinants of physicians' hospitalization rates.

The authors studied differences in the rate of hospitalization of a random sample of all general and family practitioners in the state of Washington. The study was designed to identify nonmedical factors that affect the rate at which physicians hospitalize ambulatory patients. They found that the hospitalization rate varied greatly among physicians and that this rate appeared to be sensitive to nonmedical factors. The following independent variables were significantly associated with higher rates of hospitalization while controlling for other factors: low hospital occupancy rates, low per capita income in the county, group practice, a broader scope of outpatient practice, and a busier outpatient practice. They conclude that physicians are sensitive to a range of nonmedical factors in their decision to utilize hospital resources. These findings suggest that a substantial proportion of all hospitalizations are discretionary, and that changes in practice organization or hospital occupancy rates will affect the rate of hospital use.

Data Collection↗