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PubMed2006

Posttranslational phosphorylation of mutant p53 protein in tumor development.

p53 has been called the "cellular gatekeeper" and the "genome guard," because in response to exposure to DNA-damaging agents, it induces cell-cycle arrest in G1 or apoptosis and also directly affects DNA replication. Multiple mechanisms regulate p53 activity and posttranslational modification, including multisite phosphorylation of wild-type p53, in particular. Normal functions of wild-type p53 are abrogated by mutation of this gene, and oncogenic studies have revealed that p53 mutation is among the most common genetic alteration in human cancers. It is generally accepted that mutant p53 protein may not only lose the tumor suppressor functions of wild-type p53 but also acquire additional tumorigenetic roles, including dominant-negative effects and gain of function. Although many studies have revealed such aberrant functions of mutant p53, less is known about the posttranslational phosphorylation status of mutant p53 and novel biological functions of phosphorylation in carcinogenesis.

Humans↗

PubMed2004

An empirical analysis of the demand for physician services across the European Union.

This paper presents parameter estimates for physician service equations using the "European Community Household Panel" for 12 countries covering the period 1994-1996. The focus is on two specific points: (1) the identification of behavioural similarities and differences in the demand for health services across the 12 countries; (2) the variability in demand for health services represented through a joint model for all countries. We found that there are significant differences among countries, although there are also similarities in the effect of variables such as health stock, labour situation or family structure. An important fraction of the variability in the demand for health services across countries could be explained by differences in age, income and the role of general practitioners as gatekeepers in the public health system. We found some evidence of induced demand in the decision to visit a specialist and in the number of such visits.

Adult↗

PubMed2004

Liposome-mediated adenomatous polyposis coli gene therapy: a novel anti-adenoma strategy in multiple intestinal neoplasia mouse model.

PURPOSE: Familial adenomatous polyposis is a highly penetrant, autosomal dominant disease resulting from a germline mutation of the adenomatous polyposis coli gene. Besides colorectal polyps and cancer, more than 90 percent of familial adenomatous polyposis patients also develop duodenal polyposis with an approximately 5 percent lifetime risk of malignant transformation. Because adenomatous polyposis coli protein has a "gatekeeper role" in the adenoma-carcinoma sequence, replacing its function may reduce polyp formation. We studied the functional outcome of per-oral, liposome-mediated adenomatous polyposis coli gene replacement therapy in a multiple intestinal neoplasia mouse model. METHODS: Twenty multiple intestinal neoplasia mice, heterozygous for the human homologue adenomatous polyposis coli gene, were randomly assigned to three groups: no treatment (n = 8); control plasmid containing green fluorescence protein reporter gene (n = 6); and plasmid containing the full-length adenomatous polyposis coli gene (n = 6). For the adenomatous polyposis coli-treated and green fluorescence protein reporter gene-treated groups, each mouse received the appropriate plasmid complexed with liposome, administered twice per week by oral gavage regime. Treatment lasted four weeks and all animals were killed at the end of treatment period with harvesting of intestinal tissue for polyp number estimation. RESULTS: There was a statistically significant 25 percent reduction in the total number of polyps in the adenomatous polyposis coli-treated (73.1 +/- 1.4) group compared with untreated control (97.8 +/- 5.3, P < 0.01, Tukey test) and multiple intestinal neoplasia mice treated with control green fluorescence protein gene (103.3 +/- 1.7, P < 0.01, Tukey test). CONCLUSION: Adenomatous polyposis coli gene dysfunction underlies tumorigenesis in familial adenomatous polyposis patients and multiple intestinal neoplasia mice. This in vivo study provides evidence to support a novel anti-adenoma strategy using enteral adenomatous polyposis coli gene replacement therapy.

Adenomatous Polyposis Coli↗

PubMed2006

PTSD, depression, prescription drug use, and health care utilization of Chinese workers affected by the WTC attacks.

This study assessed the impact of the World Trade Center (WTC) attacks on emotional problems, prescription drug usage, and utilization of medical and mental health services within the Chinese community in lower Manhattan. We administered a survey to 148 randomly selected Chinese workers affected by the WTC attacks in March 2003. Although nearly half of the respondents had elevated PTSD and/or elevated depression scores, only a few (4.4%) had talked to a counselor. However, nearly all (86%) reported having visited a physician at least once since September 11, 2001. Individuals with elevated PTSD scores were significantly more likely to have gone to a physician after 9/11. They were also more likely to have received prescription drugs and to indicate an interest in counseling after 9/11 than individuals with low PTSD scores. The findings highlight the role of the primary care physician as gatekeeper for mental health symptoms after a disaster. They further suggest that primary care physicians should use screening tools for depression and posttraumatic stress after a major disaster and that they should be sensitive to potential emotional problems that are associated with somatic complaints.

Adult↗

PubMed2006

Pharmacokinetic consequences of active drug efflux at the blood-brain barrier.

PURPOSE: The objective of this simulation study was to investigate how the nature, location, and capacity of the efflux processes in relation to the permeability properties influence brain concentrations. METHODS: Reduced brain concentrations can be due to either influx hindrance, a gatekeeper function in the luminal membrane, which has been suggested for ABCB1 (P-glycoprotein), or efflux enhancement by transporters that pick up molecules on one side of the luminal or abluminal membrane and release them on the other side. Pharmacokinetic models including passive transport, influx hindrance, and efflux enhancement were built using the computer program MATLAB. The simulations were based on experimentally obtained parameters for morphine, morphine-3-glucuronide, morphine-6-glucuronide, and gabapentin. RESULTS: The influx hindrance process is the more effective for keeping brain concentrations low. Efflux enhancement decreases the half-life of the drug in the brain, whereas with influx hindrance the half-life is similar to that seen with passive transport. The relationship between the influx and efflux of the drug across the blood-brain barrier determines the steady-state ratio of brain to plasma concentrations of unbound drug, K(p,uu). CONCLUSIONS: Both poorly and highly permeable drugs can reach the same steady-state ratio, although the time to reach steady state will differ. The volume of distribution of unbound drug in the brain does not influence K(p,uu), but does influence the total brain-to-blood ratio K(p) and the time to reach steady state in the brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Endoscopic techniques for treatment of gastroesophageal reflux disease: a review of abstracts from Digestive Disease Week 2003.

Endoscopic treatments of gastroesophageal reflux disease (GERD) are a new and potentially useful form of therapy for reflux disorders. This type of treatment was first introduced at Digestive Disease Week (DDW) in 2000, and the most recent DDW, in 2003, included a growing number of abstracts describing further experience with endoscopic GERD treatments. The studies are still generally open-label trials involving relatively small patient groups given a variety of unique endoscopic GERD treatments, including radiofrequency, thermal ablation, plication suturing, and polymer injection and implantation techniques. Longer patient follow-up after Stretta (Curon Medical, Sunnyvale, CA) procedures, the permanency rate of EndoCinch (Bard Interventional Products, Billerica, MA) plication sutures, and new experiences with Enteryx (Boston Scientific, Natick, MA) and Gatekeeper (Medtronic, Minneapolis, MN) procedures were highlighted at DDW 2003. Despite these unique devices with significant potential for treatment of GERD, caution was expressed concerning their clinical use in anything other than appropriately designed, scientifically validated clinical trials.

Catheter Ablation↗

PubMed1989

The consequences of current constraints on surgical treatment of appendicitis.

In this study, we sought to identify changes in the picture of a selected surgical condition during an interval of time that has brought about radical departures from previously established policies and programs. As a direct consequence, the patients take a more circuitous route to the surgeon. A significant number of patients with acute appendicitis in 1986 (37 percent) and 1987 (29 percent) suffered a prolonged delay in hospitalization or surgical referral compared with patients in 1980. This delay was accompanied by a more advanced stage of disease that ultimately caused a markedly increased morbidity (13 percent in 1986 and 24 percent in 1987, compared with 5 percent in 1980) and subsequent extended length of stay. This deterioration in patient care and failure at cost containment had previously been examined for conditions that can be operated electively. This study documents that the constraints also affect the treatment of patients whose initial condition requires urgent operative treatment. With specific relation to patients with acute appendicitis, surgeons recognize the value of the negative appendectomy. It appears the so-called gatekeepers must find a way to accept a certain negative hospitalization to referral rate. If current constraints will not allow this, the policies and programs behind the constraints should be changed.

Acute Disease↗

PubMed1994

Preventive cardiology in primary care.

Primary care physicians play a pivotal role in the successful implementation of the National Cholesterol Educational Program (NCEP) guidelines for both population and high-risk approaches to reduce blood cholesterol levels in children and adults. Increasingly, in this era of health cost containment, the primary care physician is recognized as (1) the main and sometimes the only source of health care for large numbers of individuals; (2) the affordable physician and (3) the gatekeeper for referral to medical specialists. Achievement of NCEP guidelines for cholesterol reduction, American Heart Association (AHA) guidelines for prevention of cardiovascular disease, and Year 2000 National Objectives for Health Promotion and Disease Prevention will all rely heavily on the active cooperation and support of practicing internists, pediatricians, and family/general practitioners in providing patient education, risk factor evaluation and intervention. Although the majority of primary care physicians intuitively support the concept of preventive cardiology and generally have a high level of knowledge of cardiovascular risk factors, a significant gap remains between physician knowledge and attitudes and the actual practice of preventive cardiology in clinical practice. Despite these limitations in implementation of clinical guidelines, significant progress has been made in the past decade in reaching NCEP and Year 2000 goals for population-wide cholesterol reduction.

Adult↗

PubMed1993

Does the current health care environment contribute to increased morbidity and mortality of acute appendicitis in children?

To determine whether the current "gatekeeper" controls on health care lead to an increase in treatment delay and morbidity of acute appendicitis in children, we reviewed the experience with this disease at a large children's hospital over a 10-year period. One hundred seven consecutive children 18 years and younger operated on for acute appendicitis from July 1, 1988 to June 30, 1990 were compared with 119 children with the same diagnosis from July 1, 1978 to June 30, 1980. Age, sex, race, antecedent illnesses, initial physician contact and diagnosis, time to referral and operation, pathology, morbidity, and length of stay were reviewed. The two groups were comparable in terms of age, sex, race, antecedent illnesses, and negative appendectomy rate. More patients in the recent group were initially seen in an emergency room or urgent care setting than in the previous group (62.2% v 48.5%, P = .07). The accuracy of the initial diagnosis was significantly lower in the more recent group (P = .05). No change existed between the groups in the time to a physician; however, a significant (P = .04) difference existed in the time to surgeon (41.2 hours in the earlier group v 56.4 hours in the recent group). No significant difference existed between the groups in time from surgeon to operation. Although not statistically significant, the morbidity rate was increased in the recent group (13.3% v 6.5%, P = .17).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1996

11 beta-hydroxysteroid dehydrogenases of the choriocarcinoma cell line JEG-3 and their inhibition by glycyrrhetinic acid and other natural substances.

Mineralocorticoid receptor (MR) selectivity for aldosterone is thought to be exerted by enzymes which inactivate competing glucocorticoids before they bind the receptor. Two different 11 beta-hydroxysteroid dehydrogenases (11 beta-HSD) have been described. 11 beta-HSD-1 is NADP(+)-dependent and has a Km in the micromolar range and bidirectional activity. 11 beta-HSD-2 is NAD(+)-dependent, has a Km in the nanomolar range, exhibits only oxidase activity, and colocalizes with the MR in the kidney, so is likely to serve as the gatekeeper for the MR. We have further characterized 11 beta-HSD activity in JEG-3 cells, a cell line derived from a human choriocarcinoma which was reported to have only the high affinity, NAD(+)-dependent 11 beta-HSD-2. We found that the Km for the conversion of corticosterone to 11-dehydrocorticosterone in intact cells and homogenates was about 16 nM. NAD(+)-dependent corticosterone conversion was equal in the nuclear and mitochondrial fractions and less, but significant, in the microsomal fraction. A high affinity, Km = 40 nM, NADP(+)-dependent enzyme was also found in homogenates. The subcellular distribution of this high affinity activity was greatest in the mitochondria, less in the nuclei, and even less, but still significant, in microsomes. Because of its cofactor dependency, high affinity, and different subcellular distribution, we suggest that this enzyme is neither the 11 beta-HSD-1 nor the 11 beta-HSD-2 and have named it 11 beta-HSD-3. Conversion of 11-dehydrocorticosterone to corticosterone did not occur in intact cells or in homogenates incubated with NADH or NADPH. Enzyme activity in intact cells was inhibited by glycyrrhetinic acid, carbenoxolone, progesterone, 5 beta-dihydroprogesterone, and 5 alpha-dihydroprogesterone, but not bile acids.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1985

Analysis of an addictions treatment system.

A treatment system consisting of an assessment/referral service, a detox, a mission, a hospital recovery unit, and three recovery homes was examined using a retrospective client-tracking approach over 1 year. There were 4,187 admissions to the system accounted for by 1,522 individuals; system users tended to be males, unmarried, unemployed, and in their 30s and 40s. The best predictor of readmission to the system after treatment was prior system use. Use patterns and referral data indicated that perceived gatekeepers (i.e., detoxication and assessment services) were not consistently coordinating the system and that more socially stable clients appeared to be more likely to be involved with non-addiction specific services (i.e., medical, general counselling).

Alcoholism↗

PubMed1995

Health insurance in Russia--the Kuzbass experience.

The leading pilot region for health finance reform in the Russian Federation has been adapting systems to changing economic circumstances since 1986. In 1992 a 'regulated competition' model was introduced and compulsory contributions are now routed to insurers via a central compensation fund. Hospitals are paid at standard rates (using 'clinical statistical groups') per case by diagnosis and procedure, and by outcome. Primary care is moving from fundholder polyclinics to general practitioners operating under incentives to efficient gatekeeping and provision of quality out-patient care. Private insurance co-exists for about five percent of the population, but the compulsory component is regulated through the central fund and only supplements are voluntary. The region has strong natural resources, but against a background of economic and environmental problems, a one-third increase on funding available to health over the pilot period is satisfactory, with costs of health insurance administration limited to three percent.

Consumer Behavior↗

PubMed1985

Health policy and the emerging tobacco reality.

Public policy is part of and a creator of modern environments. By intent or neglect, it affects our socially-created and natural worlds. It sets the odds for what organizations and individuals are likely to produce and consume in the form of goods, services and information, and assures how equitably these options for choice-making--and thus for life styles--are dispersed among social and economic groups. Policy is also created by environments: it is influenced by the reality of changing conditions and by the perceptions of those changes by groups who are organized to influence policymakers' views of 'reality'. The direction, humaneness and healthfulness of societal changes--to the extent that they can be guided--depend on whether new and old things are seen by policymakers in new or old ways. Creating environments conducive to health thus requires a two-pronged effort. It means: (1) developing policies that provide incentives to producers and consumers to make more healthful choices than they do today; and (2) creating a social and political climate that will encourage policymakers to choose more healthful policy options. This view point is illustrated here through an analysis of the smoking and health issue, in which changing conditions can potentially be healthfully guided, or alternatively, left to the vagaries of political and economic events. This article outlines the changing economics of tobacco, mainly as seen in its largest form in the U.S.A., its policy implications, and a political strategy to move policy in more healthful directions. Economic data reveal the tobacco sector in affluent nations as one that has been slowly declining, but now at an accelerating rate. At the same time, the tobacco economy is a growing sector in less-industrialized nations. Policy issues involve how to deal with the economic changes in health-promoting ways. Strategically this requires two simultaneous efforts. One is education/informational: posing the smoking/health issue in light of changing conditions, and addressing policy-relevant data (both economic and value-oriented) to the gatekeepers of public action and information (e.g. policymakers and media). The second is environmental/organizational, to improve the feasibility of policy changes by establishing means for transition planning in the tobacco economy.

Cross-Cultural Comparison↗

PubMed1985

Some problems with pro-competition reforms.

As the search for effective cost-containment policies continues, health care reform along pro-competition lines has gained considerable backing in the United States. By offering market competition to achieve allocational efficiency and vouchers and tax credits to achieve distributional equity, pro-competition reforms appear to satisfy what many believed were incommensurable goals. A critical review of this strategy reveals two practical difficulties, however. The first concerns the ambiguity arising from the proposals' reliance on the concept of equal access to some basic level of health care as its distributional objective and the second concerns the ethical dilemma arising from the proposals' reliance on physicians as rationers of health care. In considering the distributional goal of guaranteeing access to a basic minimum of health care, we argue that, despite its theoretical attractiveness, there exists no acceptable way of determining or justifying its content, and without a clear definition of the basic minimum there is no guarantee that any equity objective will be achieved under the pro-competition strategy. With regard to the use of physicians and other providers as society's gatekeepers, we point out that this role is in direct conflict with traditional responsibilities that patients expect providers to assume. Requiring doctors to ration services in response to market incentives may further erode the trust relationship between physicians and patients, and clearly puts the more seriously ill at a disadvantage.

Cost Control↗

PubMed1985

The role of the receptionist in general practice: a 'dragon behind the desk'?

The power and influence of receptionists in general practice has been the subject of little research. We argue that the structural position of receptionists and the nature of primary medical care give receptionists a potential discretionary role in determining access to the general practitioner. A major criterion for access is the imputed urgency of the patient's condition, which frequently involves the receptionist making a medical assessment based on only a brief verbal exchange. The paper draws on interviews with a sample of over 1000 adults about their experiences of the reception process in general practice. The receptionist's role in the following areas is examined; delay in obtaining appointments, asking the reason for surgery consultations and home visits, reducing the number of home visits by suggesting patients attend the surgery, putting patients through to speak to the doctor on the telephone and giving health advice. Patients who have experienced receptionists as an active intermediary are more likely to report interaction difficulties with receptionists. The survey data lend support to two major findings: (1) that as practices become larger and more complex receptionists operate with more rigid rules, leading to greater hostility expressed by patients towards reception staff; and (2) parents with dependent children and young adults express more antagonism, because they are more likely to experience the receptionist as a 'gatekeeper' with whom they need to negotiate to see a doctor for acute care for themselves or for their children.

Adolescent↗

PubMed1988

Do British women undergo too many or too few hysterectomies?

Hysterectomy is performed much less frequently in Britain than in North America, Australia and some European countries. Various theories have been advanced to explain this lower rate of surgery. These include: fewer health care resources (hospital beds, surgeons); much less fee-for-service medicine; differences in the attitudes of surgeons; differences in health care organisation, in particular the gatekeeping role of general practitioners; and differences in patients' expectations. This paper reviews the evidence on sources of variation and examines the extent to which hysterectomy rates vary between countries, and between small areas and social groups within Britain. Following an examination of national trends, evidence is presented from studies carried out in the Oxford region to illustrate the extent of variation in the rate at which hysterectomy is carried out and to explore the possible reasons for the differences. The article considers the health policy implications of an apparent increase in demand for hysterectomy and argues the case for a thorough evaluation of the impact of this operation on quality of life.

Adult↗

PubMed1992

Influence of bed supply and health care organization on regional and local patterns of diabetes related hospitalization.

This paper undertakes both a macro- and micro-scale analysis of the influences exerted by the health care system on patterns of hospitalization. The health disorder of diabetes mellitus is used as the case study and the analyses are based on New Zealand data sets. The article first examines the extent to which both the supply and organization of primary and secondary health care affect rates of hospitalization. The macro-scale analysis investigates the applicability of Roemer's Law to regional variations in diabetes hospitalization. The organizational control of hospital utilization via doctor gatekeeping functions and interaction between health services are then examined at the local level. This analysis assumes a population based approach using the Canterbury Register of Insulin-treated diabetic persons as the study population. Diabetes discharge rates were found to be most highly correlated with hospital bed supply in 5 of the 8 years studied (1979-1986). Stepwise regression analysis indicated area rates of diabetes hospitalization were significantly influenced by resource factors even after controlling for differences in the socio-demographic characteristics of the area populations. This confirmed the presence of Roemer's Law at the aggregate level with rates of diabetes hospitalization appearing to have more to do with the availability of medical resources than to population needs. At the local level, hospital admission patterns were found to vary by general practitioner age, practice type found to vary by general practitioner age, practice type and diabetic caseload. Overall, insulin-treated diabetic patients most likely to be hospitalized were those in the care of young doctors new to general practice, and those who attended doctors who had small diabetic caseloads. Solo practitioners had the lowest rates of patient hospitalization. There were marked disparities in patient access to specialist diabetes education and clinical outpatient services by patient age, duration of diabetes and attendance on primary care. Overall, no significant differences were found in the propensity for hospitalization between users and non-users of these specialist services. This does not imply however, service ineffectiveness but rather is indicative of the complexity of the local diabetes care organization and the differing needs of the insulin-treated diabetic population within the community as a whole.

Diabetes Mellitus↗

PubMed1995

Cardiologist versus internist management of patients with unstable angina: treatment patterns and outcomes.

OBJECTIVES: This study sought to assess the impact of generalist versus specialist direction on the pattern of care and outcome in patients admitted to the hospital for unstable angina. BACKGROUND: Physicians trained as internists or as cardiologists may have different approaches to treating patients with unstable angina. METHODS: We reviewed a prospectively collected cohort of patients discharged with a diagnosis-related group (DRG) diagnosis of unstable angina from William Beaumont Hospital, a large community-based hospital in southeast Michigan. Of 890 consecutive patients, 225 were treated by internists and 665 by cardiologists. We compared these two groups with respect to patterns of use of established pharmacotherapies for unstable angina, diagnostic testing and clinical outcome. RESULTS: Patients treated by internists less often had a previous cardiac history (53% vs. 80%, p < or = 0.0001). Internists were less likely to use aspirin (68% vs. 78%, p = 0.032), heparin (67% vs. 84%, p < or = 0.001) or beta-adrenergic blocking agents (18% vs. 30%, p < or = 0.004) in their initial management. Exercise tests were performed more frequently by internist-treated patients (37% vs. 22%, p < or = 0.001), but catheterization (27% vs. 61%, p < or = 0.0001) and angioplasty (7% vs. 40%, p < or = 0.0001) were utilized less frequently. The incidence of myocardial infarction was similar (11% vs. 9%) in the two groups, but the mortality rate tended to be higher (4.0% vs. 1.8%, p = 0.06) in the internist group. CONCLUSIONS: Patients with unstable angina treated by internists were less likely to receive effective medical therapy or revascularization procedures and experienced a trend to poorer outcome. This study does not support a positive gatekeeper role for generalists in the treatment of unstable angina.

Aged↗