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PubMed2006

Roles of the active site water, histidine 303, and phenylalanine 396 in the catalytic mechanism of the elongation condensing enzyme of Streptococcus pneumoniae.

beta-Ketoacyl-ACP synthases catalyze the condensation steps in fatty acid and polyketide synthesis and are targets for the development of novel antibiotics and anti-obesity and anti-cancer agents. The roles of the active site residues in Streptococcus pneumoniae FabF (beta-ketoacyl-ACP synthase II; SpFabF) were investigated to clarify the mechanism for this enzyme superfamily. The nucleophilic cysteine of the active site triad was required for acyl-enzyme formation and the overall condensation activity. The two active site histidines in the elongation condensing enzyme have different electronic states and functions. His337 is essential for condensation activity, and its protonated Nepsilon stabilizes the negative charge developed on the malonyl thioester carbonyl in the transition state. The Nepsilon of His303 accelerated catalysis by deprotonating a structured active site water for nucleophilic attack on the C3 of malonate, releasing bicarbonate. Lys332 controls the electronic state of His303 and also plays a critical role in the positioning of His337. Phe396 functions as a gatekeeper that controls the order of substrate addition. These data assign specific roles for each active site residue and lead to a revised general mechanism for this important class of enzymes.

Amino Acid Sequence↗
PubMed2006

Ubiquilin 1 modulates amyloid precursor protein trafficking and Abeta secretion.

Ubiquilin 1 (UBQLN1) is a ubiquitin-like protein, which has been shown to play a central role in regulating the proteasomal degradation of various proteins, including the presenilins. We recently reported that DNA variants in UBQLN1 increase the risk for Alzheimer disease, by influencing expression of this gene in brain. Here we present the first assessment of the effects of UBQLN1 on the metabolism of the amyloid precursor protein (APP). For this purpose, we employed RNA interference to down-regulate UBQLN1 in a variety of neuronal and non-neuronal cell lines. We demonstrate that down-regulation of UBQLN1 accelerates the maturation and intracellular trafficking of APP, while not interfering with alpha-, beta-, or gamma-secretase levels or activity. UBQLN1 knockdown increased the ratio of APP mature/immature, increased levels of full-length APP on the cell surface, and enhanced the secretion of sAPP (alpha- and beta-forms). Moreover, UBQLN1 knockdown increased levels of secreted Abeta40 and Abeta42. Finally, employing a fluorescence resonance energy transfer-based assay, we show that UBQLN1 and APP come into close proximity in intact cells, independently of the presence of the presenilins. Collectively, our findings suggest that UBQLN1 may normally serve as a cytoplasmic "gatekeeper" that may control APP trafficking from intracellular compartments to the cell surface. These findings suggest that changes in UBQLN1 steady-state levels affect APP trafficking and processing, thereby influencing the generation of Abeta.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Obstetricians' attitudes and opinions on sickness absence and benefits during pregnancy.

BACKGROUND: In Sweden, sick leave is taken more frequently by pregnant women than by nonpregnant women. This led us to ask if the taking of sick leave during pregnancy could possibly be explained by attitudes to sickness absence held among obstetricians working in antenatal care. METHODS: All obstetricians (n = 45) engaged in public antenatal care and at work in May 2001 in seven hospitals in South Eastern Sweden were asked to anonymously respond to questions/statements concerning their work; 87% participated. The results were presented as percent (the median value) on a visual analog scale. RESULTS: In 60% of all contacts with pregnant women issues such as working conditions, sickness absence or benefit programs were discussed besides the actual pregnancy. In 46% the obstetricians stated that they could not exactly pinpoint a correct medical diagnosis motivating a sickness certificate asked for by the pregnant woman. As the majority of the obstetricians (74%) often did not like to conform to the pregnant women's wishes, unpleasant situations were not uncommon (56%). A conflict was experienced in the dual role that the obstetrician had as the patient's confidant on the one hand and as a representative or gatekeeper for the social security system on the other. Male and female obstetricians did not differ in their opinions on their handling of pregnant women with regard to taking sick leave but for one issue, back pain. CONCLUSIONS: The high degree of work dealing with sickness absence and social benefits at the Antenatal Care Centers seems to have a negative effect on the obstetrician's evaluation of their work environment. The obstetricians' opinion is that pregnant women are sick-listed too frequently, but obstetricians comply as a rule to the women's wishes in order to avoid conflict.

Attitude of Health Personnel↗
PubMed1999

Women's characteristics and gender role attitudes: support for father involvement with children.

Women's (N = 364) personal characteristics and gender role attitudes were examined in relation to their support for father involvement with children. The respondents completed measures of trust, attitudes toward women, hostility, self-esteem, and father involvement. Nontraditional gender role attitudes, positive ratings of their own interpersonal trust, and low hostility toward men were predictive of the respondents' support for father involvement. Participant demographics (including age, marital status, and number of children) were unrelated to their views of father involvement. Results indicate the importance of considering the characteristics and attitudes women bring to the co-parental relationship in the examination of factors influencing father involvement with children. Findings are discussed within the context of mothers' primary child-care and gatekeeping roles.

Adolescent↗
PubMed1997

Coping with the crisis in psychiatric training.

No article on the future of psychiatry seems complete without mention of a sea change or a paradigm shift. The demands for cost containment and accountability have fueled a shift away from retrospective fee-for-service, solo practice to prospectively reimbursed care through giant health systems (Schreter 1993). These systems substitute less expensive, less well-trained and often less-experienced clinicians for psychiatrists whenever possible. Managed care gatekeeping utilizes psychiatrists mainly for medication management. Psychotherapy, a signature product of our profession, is being demedicalized. What will be the roles for psychiatrists in the emerging health care delivery system?

Cost Control↗
PubMed2005

Prostate-specific antigen testing in general practice: a survey among 325 general practitioners in Denmark.

OBJECTIVES: Prostate-specific antigen (PSA) is a well-known and -utilized tumor marker for prostate cancer. Elevated PSA values are not specific for prostate cancer as they may be caused by other benign conditions. PSA testing is widely used by urologists and non-urologists. Interpretation of test results is difficult but important. Referral of patients for further work-up on suspicion of prostate diseases is mainly done by general practitioners (GPs). As the GP remains the gatekeeper between the patient and the urologist in terms of diagnosing prostate diseases, basic knowledge of PSA testing is crucial. The purpose of this study was to evaluate the basic use and knowledge of PSA testing and to give an estimate of the need for further education in PSA testing amongst GPs in our area. MATERIAL AND METHODS: A questionnaire regarding PSA testing and associated needs for education was mailed to all GPs in the Northern County of Denmark. Non-respondents were contacted by mail. RESULTS: Of the contacted GPs, 90% responded. Only 28% of GPs measured PSA in all males complaining of lower urinary tract symptoms (LUTS). Of patients seen as part of a general health check-up, PSA testing was done in 10%. The median PSA value for referral to urologists for further work-up was 5 ng/ml, but the decision was influenced by PSA value (79%), age (65%) and findings on digital rectal examination (DRE) (87%). Opportunistic screening for prostate cancer was done by 14% of GPs. Of the GPs who responded, 24% stated that they did not need any further education regarding PSA testing. CONCLUSIONS: The results of this study demonstrate that PSA testing is not standardized in our area. GPs do not test patients on the basis of recommendations provided by national or international societies. PSA testing is not used as a standard test in men with LUTS, and patients are not referred to urologists at a sufficiently low PSA level to improve the early diagnosis and work-up of patients with suspected prostate cancer. However, the decision of many GPs to refer patients to urologists for further work-up is influenced by the findings of a DRE, the age of the patient and the PSA value itself. Further education regarding PSA testing amongst GPs in our area would seem to be appropriate.

Adult↗
PubMed2006

Ovarian cancer death reduction for women at high risk: workload implications for gynaecology services.

Ovarian cancer spreads early, presents late and is difficult to cure. Reducing death rates from ovarian malignancy has focussed on the unaffected females of families with a high chance of a mutant gene such as BRCA1 and BRCA2. We set up a familial ovarian cancer service in a district general hospital in the UK, serving a population of 330,000. The clinical genetics team acted as gatekeepers to the service. Risk assessment, ultrasound and biochemical screening and prophylactic oophorectomy were discussed. Gene testing was offered when appropriate. This study reviews the levels of activity for the first 8 years of the service. In all, 153 women were referred, of whom 34 (16%) did not have significant clinical histories. Of the 114 who fulfilled the UKFOCSS criteria for family history and age, four were quickly found to be gene mutation negative and 20 (17%) declined intervention. A total of 29 (25%) chose prophylactic oophorectomy and 61 (54%) chose ultrasound screening.

Ambulatory Care Facilities↗
PubMedDate not supplied

Claims and disclaimers: whose expertise counts?

Medical anthropologists have long recognized that interactions between state, clinical, scientific and lay participants transform understandings of illness. There are competing claims to knowledge in such interactions, which may be in tension with concepts of jurisdictional authority and assumptions about what constitutes different types of expertise. This paper focuses on the regulatory processes of the Food and Drug Administration in order to examine the social processes involved in negotiating and sustaining domains of knowledge across various boundaries of authority. I use the example of the way roles of commercial interests, patient interest groups and federal oversight agencies in defining and caring for health "problems" appear to be shifting with new modes of circulating information about prescription drugs. What counts as "medical expertise" when decisions about taking pharmaceuticals are moved away from former gatekeepers (physicians and insurance plans) to patients who are reframed as consumers? In this reordering new questions are raised about the location of risk and responsibility, and relations of credibility, authority and expertise.

Drug Approval↗
PubMed2004

Guidelines, evidence, and cultural factors.

OBJECTIVE: To compare four recent guidelines on uncomplicated cystitis and to examine how cultural factors may have affected recommendations. DESIGN: Descriptive study with a qualitative analysis of authors' reasons for recommendations. MATERIAL: Guidelines for general practitioners published 1999-2000 from Germany, The Netherlands, Norway, and Belgium on diagnosis and treatment of uncomplicated cystitis. Opinions of the guideline authors on the influence of local factors on the recommendations were collected before and after feedback on the differences between the guidelines. RESULTS: Few cited references were shared between the guidelines, and recommendations differed substantially, especially on diagnostic strategies and referral criteria. The authors attributed parts of the differences to local factors. German and Belgian authors stressed the need for safety in their diagnostic and therapeutic approach, while Dutch authors felt confident in their gatekeeper role and the Norwegian authors mainly relied on "the evidence". Dutch and Belgian authors perceived patients to hold power, German authors referred to the power of the sub-specialists, while the Norwegians aimed to share power with the patient through a patient-centred approach. CONCLUSION: There are substantial differences even between high-standard guidelines on the same well-defined clinical entity. The selection of literature data, and diagnostic and therapeutic recommendations, seemed to be influenced by such cultural aspects as habits, the patient's expectations, and the structure of the healthcare system.

Adult↗
PubMed1991

Role of the general practitioner in breast cancer screening in The Netherlands.

Following the advice of the Dutch National Health Council, a national screening program for breast cancer was started in 1990 in the Netherlands. All women aged 50-70 will be invited for screening by mammography in fixed or (semi)mobile screening units every 2 years. The role of the general practitioner in screening for breast cancer is described in the Dutch protocol (Standard) published in 1990 by the Dutch College of General Practitioners. Because of the role of the general practitioner/family doctor as a gatekeeper and because of the list system, every Dutch woman is known by her own general practitioner. In any given year the general practitioner will see 70% of his population. So the general practitioner is in the position to play an important role in practice and patient-centered support of breast cancer screening. The general practitioner also has an important role in the support of women with positive results. The general practitioner receives the "abnormal" results and has to explain to the woman what this means and what further investigations are necessary. There are teaching programs on screening for breast cancer for the vocational training of general practitioners and for postgraduate training.

Aged↗
PubMed1996

Teaching efficacy of a medical education module on genetic testing for cancer.

BACKGROUND: With the identification of the breast cancer susceptibility genes BRCA1 and BRCA2, clinical testing for detection of the mutated genes may be available in the near future. Primary care physicians increasingly serve as full-service providers and gatekeepers and must be aware of presymptomatic testing in order to counsel their patients appropriately. To address this educational need, a new module was incorporated into the genetics course taken by first-year medical students at the Medical College of Virginia. METHODS: The module used small groups, led by genetics faculty and members of the Virginia Breast Cancer Foundation, for discussion of case examples. The medical students' knowledge of and attitudes toward cancer and predictive genetic testing were assessed by a pretest and a posttest. RESULTS: After the module, knowledge scores increased by 27%, and significant changes were seen in the students' attitudes toward issues such as the regulation of testing availability and the psychological effect of testing. Most students consistently felt that predictive genetic testing is beneficial, that they would have the testing themselves, that genetic counseling should be required for testing, and that insurers' access to genetic testing results should be limited. Overall, the module was received favorably by all participants. CONCLUSIONS: Small-group discussion of relevant case examples increases knowledge and awareness of issues regarding presymptomatic genetic testing for breast cancer.

Breast Neoplasms↗
PubMedDate not supplied

The illusive phantom: does primary care meet patient need following limb loss?

PURPOSE: Anecdotal evidence suggests that General Practitioners (GPs) vary in their understanding of phantom pain and associated factors in amputees. This has implications in that the GP's conception of the problem will determine what treatment or referral is offered. METHOD: The present study aimed to explore GP's knowledge and understanding of phantom limb pain using a postal questionnaire. A sample of 129 GPs responded resulting in a response rate of 38%. RESULTS: The results suggest that GPs underestimate the prevalence, intensity and duration of phantom and residual limb pain. Moreover, inconsistencies in the reasons given for referral to specialist services for the management of phantom pain were reported. CONCLUSION: These findings have serious implications for the management of phantom limb pain, disability and psychological distress in amputees in that GPs not only provide first line treatment, but are also the gatekeepers for referral to other services. Given this, the role of other professionals within the primary health care team may prove an additional resource for providing both support and accurate information to amputees in the community.

Adult↗
PubMed2003

Mixed chimerism of bone marrow vessels (endothelial cells, myofibroblasts) following allogeneic transplantation for chronic myelogenous leukemia.

Experimental findings support the hypothesis that within the functional network of the bone marrow (BM) microenvironment the endothelial cells (ECs) exert a pivotal role as gatekeepers by controlling the trafficking and homing of progenitor cells. However, little information is available concerning the origin of ECs after allogeneic bone marrow transplantation (BMT) in CML. To determine the extent of mixed chimerism (MCh) a simultaneous immunohistochemical and fluorescence in-situ hybridization (FISH) study was performed on BM biopsies derived from patients following sex-mismatched BMT with full unmanipulated BM. ECs were identified by their staining with CD34 and the myofibroblasts (MFs) of large vessels were labeled by an antibody against alpha-smooth muscle actin. For sex-typing and demonstration of the bcr/abl fusion product appropriate commercially available probes and detection systems were applied. Contrasting a total congruence of labeling in control samples five patients showed donor type ECs in the early posttransplant period in about 20%. In the remaining four patients the amount of donor type ECs increased slightly after the third month up to 30%. A total of 26 MFs could be identified lining large capillaries and arterioles that exclusively revealed a host origin. Following successful engraftment only very few of the persistent host-derived ECs also displayed the bcr/abl gene. In five patients, a conversion of MCh from donor to host type ECs was recognizable during the evolution of leukemic relapse. This finding was accompanied by a bcr/abl rearrangement of about 10% of these cells. In conclusion, following myelo-ablative therapy, a survival of a considerable number of ECs and MFs of the vessel walls has been found implying persistence of host-derived vascular structures of the BM stroma. However, in only a small proportion bcr/abl+ ECs and thus minimal residual disease was detectable. Evolution of leukemic relapse was characterized by conversion of MCh with almost total loss of donor type ECs and increase in number of bcr/abl+ ECs.

Adult↗
PubMed2003

Primary care nurse practitioners and the interface with secondary care: a qualitative study of referral practice.

In the United Kingdom nurse practitioners are assuming responsibilities traditionally considered to be within the domain of general practitioners. Important amongst these is the referral of patients to medical consultants in secondary care, a responsibility commonly associated with the general practitioner's role as 'gatekeeper' to health care. This paper describes a study designed to identify issues raised by the challenge that a developing nursing role presents to interprofessional working at the interface between primary and secondary care. When invited to comment, study participants (nurse practitioners, nurse educators, medical consultants and general practice registrars) related nursing referrals to issues associated with professional boundary changes, namely: teamwork, regulation of practice, communication, professional conflict and professional relationships. This paper discusses the views of primary and secondary care practitioners about who should take responsibility for the referral of patients in the light of concerns raised about professional competence and accountability. Individual nurse practitioners and their colleagues have found pragmatic ways to manage their work however, although UK government policy supports development of advanced clinical nursing, there remains much work to be done to provide the professional and legal infrastructure to support the role.

Adult↗
PubMed2006

Physicians' expectations regarding registered nurses caring for older people living in sheltered housing, retirement homes and group dwellings.

The aim of this study was to illuminate the meaning of the physicians' expectations regarding registered nurses who are responsible for the care of older people living in sheltered housing, retirement homes and group dwellings. A phenomenological-hermeneutic method was used for the analysis. Twelve physicians from two municipalities in Sweden were interviewed. The naive reading of the interviews characterizes the physicians' expressed views of nurses by using metaphors such as "the extended arm", "gatekeeper" and "belonging to a no-man's land". In the structural analysis, explanations of the metaphors are given. The new understanding was that the physicians also expect registered nurses to be able to switch between keeping a distance and being close to older people. When registered nurses have this skill, the physicians have a "we" feeling towards the nurse. The paper provides insights into the physician-nurse relationship, in the context of residential care in Sweden.

Aged↗
PubMed2003

Recruitment of rural community-dwelling older adults: barriers, challenges, and strategies.

The significant increase in the number of older adults in the USA, particularly in rural areas, has signaled the need for more research to address the health care needs of this complex, heterogeneous, and vulnerable population. However, accessing older adults in rural areas presents an especially difficult challenge for gerontological researchers. Barriers can include the normal physiological changes that accompany aging, prevalence of chronic illness and medication use, lower literacy rates, transportation issues, and a distrust of 'outsiders' and research in general. Specific strategies that may facilitate participation include the use of gatekeepers to gain entry, increased personal contact by researchers sensitive to the unique needs of older adults, and other media approaches tailored to the rural community. Understanding the characteristics of rural older adults, along with careful planning of recruitment strategies, is crucial to obtaining adequate participation and the acceptance of future research efforts.

Aged↗
PubMed2005

Re-evaluating the role of the MFM specialist: lead, follow, or get out of the way.

OBJECTIVE: To assess the effect of sub-specialty prenatal care provided to high-risk obstetrical patients in a community perinatal center as a function of whether consultation and referral to a Maternal-Fetal Medicine (MFM) sub-specialist was at the discretion of the generalist, required by the insurance carrier, or by patient choice. METHODS: Demographics, management, and perinatal outcomes for high-risk patients managed exclusively by MFM were compared with those managed by generalists who were later referred to MFM after problems arose. RESULTS: Despite similar demographics, high-risk patients managed exclusively by a single MFM had less prematurity, lower cesarean section rates, fewer low 5-minute Apgar scores (1.3% vs. 5.5%, p < 0.001), and lower perinatal mortality rates (8.0/1000 vs. 47.6/1000, p < 0.001) than those referred at a later date. CONCLUSIONS: In this setting, earlier MFM care resulted in better outcomes. These data suggest that the 'gatekeeper' model of generalist to MFM might be better the other way around.

Adult↗
PubMed2004

Outpatient drug treatment program directors' hepatitis C-related beliefs and their relationship to the provision of HCV services.

The hepatitis C virus (HCV) continues to penetrate populations within the United States, especially within the drug-abusing population. Therefore, drug users need access to HCV testing and medical care, and drug treatment programs are well situated to provide these services. Because directors of these programs are gatekeepers who can influence decisions about service provision, their beliefs about the value of providing particular services for drug treatment program patients are of considerable importance. Directors of 121 outpatient drug treatment programs throughout the United States responded to an in-depth telephone survey that included questions on their beliefs about providing HCV services in drug treatment programs. We constructed an eight-item scale to examine these beliefs and investigated the relationship between them and the actual HCV services offered. Overall, directors were moderately supportive of the provision of HCV medical services (on-site or through referral) during drug treatment. Our findings indicate that there is a positive significant relationship between director's beliefs and the provision of HCV antibody testing, follow-up testing, and the provision of HCV medication.

Adult↗