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Dr. Alvan R. Feinstein, late editor of the Journal of Clinical Epidemiology, is remembered by his fellow editor in this article. His role is highlighted as an innovative gatekeeper of clinical and epidemiological communications and as an effective secret mentor of his younger partner. The profile of his editorial practice is summarized as "six commandments" and the Golden Rule of pursuing attainable excellence.
The molecular basis of the intrinsic vulnerability of the compliant right ventricle to chronic pressure overload is poorly understood. Extensive apoptosis, possibly coupled with aberrant cell cycle reentry, in response to unrestrained biomechanical stress may account for this phenotypic flaw. To address this issue we have studied changes in expression of the cell cycle and apoptosis regulators in the right ventricle following induction of pulmonary hypertension in the rat by injection of monocrotaline. Hypertrophy, apoptosis and cell cycle events, as well as expression of their regulator genes were documented during a period of 31 days. The hypertrophy index reached 127% at day 31. At the early stage both apoptosis and cell proliferation pathways were coincidentally activated. The level of cyclin A and E transcripts steadily increased, the labeling index was 4.8% at day 31, and expression of the caspase-3 gene peaked at day 14. Until day 21 execution of apoptosis was prevented, probably by a high level of Bcl-2. At this time point Bcl-2 collapsed, cyclin D1 was upregulated, the differentiation gatekeeper p27Kip1 was downregulated, pro-caspase-3 was activated and extensive apoptosis developed. These results indicate that the right ventricle is especially vulnerable to apoptotic pressure-dependent stimuli, and that the cell cycle and apoptosis pathways were co-activated in this experimental model.
Non-pituitary tumors that produce adrenocorticotropic hormone (ACTH) exhibit resistance to the normal feedback effects of glucocorticoids on proopiomelanocortin (POMC) gene expression. This glucocorticoid resistance is typically complete, although some tumors show only relative glucocorticoid resistance in the clinical setting. The molecular mechanisms responsible for these clinical pathophysiologic observations are unknown, but might include glucocorticoid receptor defects or aberrant expression of enzymes or transporters that exclude glucocorticoids from access to their intracellular receptors. We examined whether ACTH-producing non-pituitary tumor cells might express 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the principal 'gatekeeper' enzyme known to metabolize glucocorticoids. 11Beta-HSD mRNA and enzyme activity were assessed in DMS-79 cells, a line derived from an ACTH-producing small cell lung cancer. RT-PCR studies showed expression of mRNA encoding 11beta-HSD2 but not 11beta-HSD1 in DMS-79 cells. Control human fibroblasts expressed predominantly 11beta-HSD1 but also had detectable 11beta-HSD2 mRNA, while HepG2 hepatoma cells also expressed only 11beta-HSD2 mRNA. Whole cell assays in DMS-79 cells revealed 11beta-HSD activity with a Km for cortisol of 26.1 +/- 9.0 nM and Vmax of 57.0 +/- 5.9 pmol/h/mg protein. HepG2 cells expressed a similar high affinity enzyme activity, while control fibroblasts expressed 11beta-HSD activity with a Km for cortisol of 652 nM. Conversion of cortisol to cortisone in DMS-79 cells was inhibited to 7% of baseline by addition of 10 microM glycyrrhetinic acid. Dexamethasone (20 nM) was converted to a single product in DMS-79 cells at a rate of 17.2 pmol/h/mg protein; this activity was also inhibited by glycyrrhetinic acid. We conclude that DMS-79 cells express 11beta-HSD2. While DMS-79 cells harbor additional defects in glucocorticoid signaling, these data suggest that expression of 11beta-HSD2 might contribute to the development of the glucocorticoid-resistant phenotype of some ACTH-producing tumors.
Periglomerular cells in the olfactory bulb are the 'gatekeepers' of the olfactory system. A recent study shows that these cells inhibit themselves by releasing GABA from their own dendrites.
Neurons that connect the two sides of the nervous system project their axons across the midline. New studies provide evidence for a conserved gatekeeping mechanism that controls this midline crossing.
Nicaragua's Penal Code permits "therapeutic abortion" without defining the circumstances that warrant it. In the absence of a legally clear definition, therapeutic abortion is variously considered legal only to save the woman's life or also to protect the health of the woman, and in cases of fetal malformation and rape. This paper presents a study of the theory and practice of therapeutic abortion in Nicaragua within this ambiguous legal framework. Through case studies, a review of records and a confidential enquiry into maternal deaths, it shows how ambiguity in the law leads to inconsistent access to legal abortions. Providers based decisions on whether to do an abortion on women's contraceptive behaviour, length of pregnancy, compliance with medical advice, assessment of women's credibility and other criteria tangential to protecting women's health. The Nicaraguan Society of Obstetrics and Gynecology aimed to clarify the law by developing a consensus among its members on the definition and indications for therapeutic abortion. If the law designates doctors as the gatekeepers to legal abortion, safeguards are needed to ensure that their decisions are based on those indications, and are consistent and objective. In all cases, women should be the ultimate arbiters of decisions about their reproductive lives, to guarantee their human right to life and health.
PURPOSE: The purpose of this study was to identify the factors that contributed to intervention effectiveness in acquired immunodeficiency syndrome (AIDS) prevention projects targeting youth. METHODS: Eleven AIDS prevention projects funded by the Robert Wood Johnson Foundation whose target populations consisted of at least 60% youth were studied. A blended methodology resulted in quantitative data (i.e., survey responses) from all 11 projects supplemented with qualitative data (i.e., open-ended interviews) drawn from in-depth site visits to six projects. RESULTS: Projects reported using a mean of 16.6 intervention activities (selected from a list of 30). Six activities were used by all 11 projects. Small group discussions were rated as one of three most effective activities by 72.7% of the projects that used them. Project staff identified three elements of effective interventions: involvement of peer educators, recognition of the role of adults (e.g., parents, teachers), and use of structured settings to gain access to the target population (e.g., schools, clubs). CONCLUSIONS: The most powerful strategies described by project staff for reaching adolescents at risk for human immunodeficiency virus (HIV) transmission also bring considerable challenges. Opportunity costs associated with using peer educators, gatekeeper support, and structured settings may include limited control of the message, impaired credibility, and failure to reach those youth at greatest risk of HIV infection, respectively. Health educators will do well to consider the advantages and disadvantages of these factors when developing, implementing, and evaluating AIDS prevention programs for youth.
Health maintenance organizations (HMO) and nuclear cardiology represent mutual threats and mutual opportunities for each other. On the one hand, nuclear cardiology represents a cost center with HMOs exerting tremendous financial pressure on nuclear cardiology programs. On the other hand, nuclear cardiology can act as a sage gatekeeper to the cardiac catheterization laboratory and help HMOs effectively control the health care of an increasing percentage of the population. Through the process of negotiation, of determining each other's needs, an accommodation can take place between the two. The ability to correlate scan results with coronary angiography provides individual nuclear cardiology programs with the opportunity to demonstrate their accuracy. A Nuclear Cardiology Report Card based on these data can be developed for use, with HMOs creating the opportunity to compete not only on price but also on value. Carved out capitation rates for nuclear cardiology can be estimated on the basis of actual experience with an HMO population and by extrapolation from test frequency of the U.S. population. The financial disincentives of capitation and of managed care challenge the physician-patient relationship. Advocacy of the role of nuclear cardiology and an understanding of negotiation strategies can aid nuclear cardiologists in their attempts to provide quality care with commensurate compensation.
Overall, the face of public health nursing has changed dramatically during the past several decades, and perhaps the most significant influence-for good or ill-has been the advent of managed care in this specialized domain of nursing practice. As managed care organizations supplant physicians as the gatekeepers of care, deciding when, in what form, and at what cost care is provided, three major changes have occurred in the home care arena. These changes affect patients, their families, the location of their care, and the roles and responsibilities of the health care team. The home care landscape, regardless of geographic setting, has dramatically changed for all participants. In the continuing effort to reduce the high costs of health care, managed care companies are mandating that patients be discharged from the hospital earlier, shifting care to the home. In essence, the home has become a "step-down" unit of the hospital. Patients are being sent home sicker, with higher acuity levels, and at risk for increased morbidity and readmission rates. Families are taking on more responsibility for care provided in the home. In addition, the role of the visiting nurse has changed. She is now a member of an expanded home care team. She acts in a supervisory capacity more often, must contend with complex clinical problems, and often must oversee the use of high-tech equipment. She is no longer seen as the health care team member who wears squeaky blue shoes and renders all home care from the depths of her little black bag, similar to pulling the rabbit out of the hat. She is the leader of a team that includes numerous professional providers.
Selective infection of peripheral nerves is a unique property of Mycobacterium leprae that results in serious injury, but its basis is unexplained. Recent evidence from infected armadillos suggests that endothelial cells of peripheral nerve vasculature may be the gatekeepers by which M. leprae infects nerves. The pathogenesis of neuropathy in leprosy may thus entail a dynamic sequence of adhesion, immunologic, and inflammatory processes involving peripheral nerve endothelial cells.
Assisted reproductive technologies (ARTs) have been the focus of considerable debate in which a range of social issues has been addressed, yet the question of who is eligible for ART, who can get access, who is excluded and by what means, has received little attention in comparison with other issues. In Australia social policies presently exist in some (but not all) states which address this question, however several recently publicised cases have highlighted the need for an examination of inclusion/exclusion practices from a social justice perspective. This paper seeks to explore the issue of access and eligibility for ART with a particular interest in exposing the contradictions, inconsistencies and assumptions inherent in arguments put forward for particular inclusions and exclusions. It is my contention that social policy relating to criteria for eligibility and access to ART invests the medical profession with a gatekeeping role which holds the power to define and create different classes of women. Moreover, discourses of 'medical indication' and the 'best interests of children' intersect to inscribe a form of discursive eugenic practice which in turn sustains sexism and discrimination against childless women. Finally, this paper seeks to alert the nursing profession to requirements emerging from social policy which influence practice, interfere in client-nurse relationships, and may ultimately result in unethical conduct.
This paper examines the 'survival' strategies adopted by lower income groups seeking to cope with the costs of primary care. Two surveys, one of the health and health service concerns of clients of an inner city voluntary welfare agency, and another of how 114 general practitioner (GP) surgeries in Christchurch, New Zealand aided patients in financial distress, were conducted in October-December, 1997. Patients adopted a variety of strategies, both active and passive, with delays in obtaining medications and seeking financial help from GPs being the most common. Although less important, high rates of switching GPs occurred. There was evidence of geographical variation in the strategies adopted by patients and practices as well as of the effects of such strategies given that considerable levels of unmet need remain. I conclude that more attention should be paid to the gatekeeper role of GPs and how their actions in different social contexts may result in inequalities in service provision to low income patients and outcomes of care.
Flawed expert scientific testimony has compromised truth finding in American litigation, including in medical malpractice and in product liability cases. The Federal Rules of Evidence and the Supreme Court in Daubert and other cases have established standards for testimony that include reliability and relevance, and established judges as gatekeepers. However, because of lack of understanding of scientific issues, judges have problems with this role, and juries have difficulties with scientific evidence. Professionals and the judiciary have made some advances, but a better system involving the court's use of neutral experts and a mechanism to hold experts accountable for improprieties is needed.
For the past decade, polyketide synthases have presented an exciting paradigm for the controlled manipulation of complex natural product structure. These multifunctional enzymes catalyze the biosynthesis of polyketide natural products by stepwise condensation and modification of metabolically derived building blocks. In particular, regioselective modification of polyketide structure is possible by alterations in either intracellular acyl-CoA pools or, more commonly, by manipulation of acyl transferases that act as the primary gatekeepers for building blocks.
The host response is the outcome of an interplay between innate immunity, adaptive immunity (Th1, Th2, T regulatory cells, B cells and antibodies) and fungal virulence factors. Dendritic cells are the gatekeepers between innate and adaptive immunity and have been the intense focus of recent studies on innate immunity to fungi because of their ability to distinguish between different forms of a fungal species, to drive Th1 versus Th2 versus T regulatory responses, and potentially be modulated by fungal products. New mechanisms have been described by which anti-fungal antibodies can modulate infection and augment T cell immunity. Th1 responses are central to limiting infection with many fungi; thus, a great deal of attention has been focused recently on the antigen(s) that trigger such a response.
The ocular inflammatory diseases dry eye and allergic conjunctivitis are mediated by CD4+ T cells. Th1 cells secrete interferon (IFN)-gamma and are implicated in mediating the disease process in dry eye. Allergic conjunctivitis has been classically defined as a Th2 disease because of the predominance of Th2 cytokines interleukin (IL)-4 and IL-13. A multi-hit antigen challenge mouse model of allergic conjunctivitis provides evidence that IFN-gamma, a Th1 cytokine, acts as an endothelium gatekeeper by regulating endothelial expression of vascular adhesion molecule-1 required for inflammatory conjunctival cell infiltration. Current research encourages an in-depth evaluation of the exact role Th1 and Th2 cells play in ocular inflammation.
The gene p53 is a critical tumor suppressor that can respond to multiple signals of cellular gatekeepers for growth and division. The mdm2 gene is one of the downstream target genes for transcriptional activation by the product of p53 tumor suppressor gene. Transactivation of mdm2 gene is represented by the presence of a functional P53 protein. To understand the biological function of mutant p53 in tumorigenesis, we constructed a number of p53 mutants by site-directed mutagenesis (H179Y, L194R, S240R, R249S, A276D, E286Q), followed by characterization of each P53 mutant's ability to transactivate mdm2, bax and p21waf. The transactivation properties of p53 mutants were compared by co-transfection with pGL-3-mdm2, pGL-3-bax and pGL-3-p21waf into the P53 null cell line H1299 derived from a non-small cell lung carcinoma. Among them mt p53 S240R and E286Q were shown to have enhanced transactivating activity of pGL3-mdm2, at about 43.2 and 28.2% of the wt p53 vector, respectively, while the remaining four had nearly the same level of activity as the negative control did. Furthermore, data indicated that mt p53 S240R had as high an ability to suppress the growth of the p53 null cell line H1299 as wild type p53. Therefore, mutant p53 alone is an insufficient indicator of poor prognosis. Instead, functional p53 may affect lung cancer prognosis.
Lipoprotein lipase (EC 3.1.1.34; LPL) is a key enzyme regulating the disposal of lipid fuels in the body. It is expressed in a number of peripheral tissues including adipose tissue, skeletal and cardiac muscle and mammary gland. Its role is to hydrolyse triacylglycerol (TG) circulating in the TG-rich lipoprotein particles in order to deliver fatty acids to the tissue. It appears to act preferentially on chylomicron-TG, and therefore may play a particularly important role in regulating the disposition of dietary fatty acids. LPL activity is regulated according to nutritional state in a tissue-specific manner according to the needs of the tissue for fatty acids. For instance, it is highly active in lactating mammary gland; in white adipose tissue it is activated in the fed state and suppressed during fasting, whereas the reverse is true in muscle. Such observations have led to the view of LPL as a metabolic gatekeeper, especially for dietary fatty acids. However, closer inspection of its action in white adipose tissue reveals that this picture is only partially true. Normal fat deposition in adipose tissue can occur in the complete absence of LPL, and conversely, if LPL activity is increased by pharmacological means, increased fat storage does not necessarily follow. LPL appears to act as one member of a series of metabolic steps which are regulated in a highly coordinated manner. In white adipose tissue, it is clear that there is a major locus of control of fatty acid disposition downstream from LPL. This involves regulation of the pathway of fatty acid uptake and esterification, and appears to be regulated by a number of factors including insulin, acylation-stimulating protein and possibly leptin.