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PubMed2006

T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2.

Adaptor proteins positively or negatively regulate the T cell receptor for antigen (TCR) signaling cascade. We report that after TCR stimulation, the inhibitory adaptor downstream of kinase (Dok)-2 and its homologue Dok-1 are involved in a multimolecular complex including the lipid phosphatase Src homology 2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP)-1 and Grb-2 which interacts with the membrane signaling scaffold linker for activation of T cells (LAT). Knockdown of LAT and SHIP-1 expression indicated that SHIP-1 favored recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed their negative control on Akt and, unexpectedly, on Zap-70 activation. Our findings support the view that Dok-1 and -2 are critical elements of a LAT-dependent negative feedback loop that attenuates early TCR signal. Dok-1 and -2 may therefore exert a critical role in shaping the immune response and as gatekeepers for T cell tolerance.

Adaptor Proteins, Signal Transducing↗
PubMed1999

A comprehensive plan for managed care of patients infected with human immunodeficiency virus.

Medicaid is rapidly moving toward managed care throughout the United States and will have a major impact on care programs for those infected with human immunodeficiency virus (HIV). The experience at the Johns Hopkins HIV Care Service is an example of the transition from fee-for-service to managed care. The Maryland Medicaid program, which has required enrollment of all Medicaid recipients since June 1997, uses an adjusted payment rate and separately funds protease inhibitors. Elements that made the transition to a managed care organization possible included the early development of a comprehensive network of services and a database showing that historical Medicaid payments were low compared with the statewide experience. Our Medicaid managed care program promotes unlimited access to specialists, rejects the "gatekeeper" concept for any service, and includes an open formulary. Nevertheless, it is uncertain that the services now provided can be sustained with anticipated reductions in payments that seem inevitable with Medicaid policies here and nationally.

Baltimore↗
PubMed2000

Racism and medical science in South Africa's Cape Colony in the mid- to late nineteenth century.

Racism has been a particular focus of the history of Western medicine in colonial South Africa. Much of the research to date has paradoxically interpreted Western medicine as both a handmaiden of colonialism and as a racist gatekeeper to the benefits of Western medical science. This essay suggests that while these conclusions have some validity, the framework in which they have been devised is problematic. Not only is that framework contradictory in nature, it underplays differences within Western medicine, privileges the history of explicit and intentional racial discrimination in medicine, and encourages a separate analysis of racism in law, in the medical profession, and in medical theory and practice. Using the example of the Cape Colony in South Africa, this paper shows how legislation, class, institutional setting, and popular stereotypes could influence the form, timing, and degree of racism in the medical professional, and in medical theory and practice. It also argues for an analytical distinction between 'racist medicine' and 'medical racism.'

Colonialism↗
PubMed2003

Methodological issues and controversies in clinical trials with child and adolescent patients with bipolar disorder: report of a consensus conference.

OBJECTIVE: To achieve consensus among researchers, pharmaceutical industry representatives, federal regulatory agency staff, and family advocates on a template for clinical trials of acute mania/bipolar disorder in children and adolescents. METHOD: The American Academy of Child and Adolescent Psychiatry, in collaboration with Best Practice, convened a group of experts from the key stakeholder communities (including adult psychiatrists with expertise in bipolar disorder) and assigned them to workgroups to examine core methodological issues surrounding the design of clinical trials and, ultimately, to generate a consensus statement encompassing: (1) inclusion/exclusion criteria, (2) investigator training needs and site selection, (3) assessment and outcome measures, (4) protocol design and ethical issues unique to trials involving children/adolescents, and (5) regulatory agency perspectives on these deliberations. RESULTS: Conference participants reached agreement on 18 broad methodological questions. Key points of consensus were to assign priority to placebo-controlled studies of acute manic episodes in children and adolescents aged 10-17 years, who may or may not be hospitalized, and who may or may not suffer from common comorbid psychiatric disorders; to require that specialist diagnostic "gatekeepers" screen youths' eligibility to participate in trials; to monitor interviewer and rater competency over the course of the trial using agreed upon standards; and to develop new tools for assessment, including scales to measure aggression/rage and cognitive function, while using the best available instruments (e.g., Young Mania Rating Scale) in the interim. CONCLUSIONS: Methodologically rigorous, large-scale clinical trials of treatment of acute mania are urgently needed to provide information regarding the safety and efficacy, in youth, of diverse agents with potential mood-stabilizing properties.

Adolescent↗
PubMed2004

The WISEWOMAN projects: lessons learned from three states.

BACKGROUND: The WISEWOMAN program provides chronic disease risk factor screening, lifestyle interventions, and referrals to financially disadvantaged women who participate in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). Three states (Arizona, Massachusetts, and North Carolina) participated in Phase One (1995-1998). METHODS: Using a case study approach, we reviewed documents and conducted telephone interviews to compare the three projects' design and execution. The interviews, carried out in mid-2002, involved a convenience sample of project coordinators, project directors, researchers, and one CDC project officer (n = 9). RESULTS: Many providers were overwhelmed by WISEWOMAN's research component and disliked its lack of flexibility. Researchers emphasized that high-quality evaluation requires resources and attention. Informants described the challenges of integrating WISEWOMAN with state BCCEDP programs that are in varying development stages and recommended changes in organizational culture and provider practices. Regarding implementation, informants emphasized the need for adequate and appropriate planning, buy-in, training, professional support, and outreach. Our sample also noted that WISEWOMAN projects tend to be labor intensive. CONCLUSIONS: WISEWOMAN projects face challenges of integrating clinical and lifestyle interventions, reaching beyond a focus on individuals, marshaling substantial resources, and introducing complex interventions into stretched healthcare environments. The three Phase One projects were deemed successful in reaching underserved women, developing a more comprehensive women's health model, strengthening linkages to primary healthcare, experimenting with innovative behavioral interventions, and tapping into women's roles as social support providers and family/community gatekeepers.

Adult↗
PubMed2005

Integrated substance use and mental health treatment for adolescents: aligning organizational and financial incentives.

The high prevalence of the dual diagnosis of mental and substance use disorders (SUD) has been increasingly documented for both adolescents and adults (Crowley and Riggs 1995; Kandel et al. 1999; Whitmore et al. 1997). For more than a decade, the National Institute of Drug Abuse (NIDA) has included integrated treatment of comorbid psychiatric disorders as one of nine core treatment principles (National Institute on Drug Abuse 1999). Despite empirically supported practice guidelines, implementation of integrated treatment has been slow (New Freedom Commission on Mental Health 2003; U.S. Department of Health and Human Services 1999). In response to the growing call for integrated treatments and systems of care, this paper: (1) identifies systemic and economic barriers that have impeded widespread implementation of integrated care for adolescents with co-occurring SUD, specifically the supply of treatment providers, shifting priorities of gatekeepers to specialty care, and financing streams; and (2) describes possibilities for aligning economic incentives in order to facilitate the dissemination and implementation of integrated care for adolescents with co-occurring SUD.

Adolescent↗
PubMed1998

Biochemical and genetic evidence for complex formation between the influenza A virus NS1 protein and the interferon-induced PKR protein kinase.

The interferon (IFN)-induced protein kinase (PKR) functions as a gatekeeper of mRNA translation initiation and is, therefore, a key mediator of the host IFN-induced antiviral defense system. Many viruses have invested countermeasures against PKR. Some apparently use more than one mechanism. The influenza virus can repress PKR activity through the use of at least two factors, the cellular P58IPK protein and the viral NS1 protein. The exact mode of action of the latter has not been established. Here, using a coprecipitation assay, we found that PKR could form a complex with NS1 in crude cell extracts prepared from influenza virus-infected HeLa cells. The NS1-PKR interaction was verified by using the yeast two-hybrid system and an in vitro binding assay. Deletion analysis mapped the NS1 binding site to the N-terminal 98 residues of PKR regulatory region. Furthermore, an NS1 mutant, which lacks PKR inhibitory activity, did not bind PKR. Finally, the functional role of NS1 in PKR inhibition was substantiated using an in vivo assay for PKR activity. These results support the role of NS1 in PKR modulation during viral infection that is mediated through a complex formation between the two proteins.

Antiviral Agents↗
PubMed2005

Providers' acceptance of telehospice.

BACKGROUND: This research was conducted as part of a telehospice study conducted by researchers at Michigan State University, in a partnership with Hospice of Michigan. The study took place from March 2000 through December 2002. OBJECTIVE: One of the primary objectives of the study was to learn more about how providers feel about the provision of telemedicine services, in this case telehospice. Of particular importance was learning more about how providers' perceptions of services could change over the course of the project as they became more familiar and comfortable with providing telehospice services. Finally, researchers were interested in how the providers' perceptions of telehospice system might influence utilization. SETTING/SUBJECTS: Four Hospice of Michigan offices took part in this telehospice study, two in rural areas and two in urban settings with a total of 187 patients receiving telehospice care. Health providers who offered telehospice services were recruited to share information about their perceptions of the technology. MEASUREMENTS: Providers were surveyed at the beginning and end of the project to track their perceptions of telehospice services. Five focus groups with providers were also conducted over the course of the project to allow providers to elaborate their thoughts and perceptions in greater detail. RESULTS: Actual utilization of the telehospice system did not have a significant impact on perceptions of services; for the most part, providers began the project with pre-conceived notions about the technology and these perceptions held over the course of the project. Even providers who praised the level of training and technical support and who were able to cite success stories did not display a significant change in attitudes toward telehospice. Providers did express concern regarding how telehospice would impact current aspects of their job such as autonomy or mileage reimbursement. CONCLUSIONS: Study results indicate that providers serve as gatekeepers to a new technology and manner of providing care. Telehospice services in this project were primarily provided by a handful of enthusiastic adopters. The results of this study provide important implications if telehospice care is to disseminate for general use among hospice recipients.

Attitude of Health Personnel↗
PubMed2004

Restriction in activity associated with fear of falling among community-based seniors using home care services.

BACKGROUND: Fear of falling may lead to avoidance of activities for seniors, even though they may be able to perform these activities. Specific risk factors for fear of falling that are amenable to change among various populations have been identified within the literature; however, detailed information about the risk factors for fear of falling, specifically among community-based seniors receiving home care services, is limited. OBJECTIVE: The aim of this cross-sectional study was to examine the factors associated with restriction of activity resulting from fear of falling among 2,300 seniors receiving home care services. PARTICIPANTS: All participants (n = 2,304) in this study were receiving home care services between 1999 and 2001 from a sample of 10 volunteering community-based agencies (Community Care Access Centres) representing the major geographic regions of Ontario, Canada. Community care access centres act as gatekeeping organisations assessing need and contracting out for a broad range of community-based services. MEASUREMENTS: The Minimum Data Set for Home Care, a comprehensive and standardised assessment tool used to evaluate the needs and ability levels of older adults utilising home care services, covers several key domains, such as service use, function, health and social support. Nurses trained to administer the Minimum Data Set for Home Care assessed each of the participants within their homes. RESULTS: Of the 2,304 seniors within the study, 41.2% of participants expressed they restricted their activity for fear of falling. Percentages reporting fear of falling within the literature are considerably lower than the presentfindings, and probably attributable to the frailer, home care population within the present study. In the final logistic regression model, being female, having various impairments/limitations, lack of support and being a multiple faller significantly increased risk of fear of falling, whereas individuals that used antipsychotics and individuals that had Alzheimer's disease were less likely to report restricting their activity. CONCLUSIONS: The results from this study provide information about a group void in the literature pertaining to activity restriction from fear of falling - community-based seniors receiving home care services. The comprehensive nature of the Minimum Data Set for Home Care allowed for a myriad of factors to be assessed and subsequently analysed with respect to the outcome variable. The inclusion of items on falls, fear of falling, and risk factors for both adverse outcomes means that home care professionals using this instrument will have a unique opportunity to identify and respond to problems that have an important impact on the client's quality of life.

Accidental Falls↗
PubMed2025

Smarter stomata: emergent technologies unlocking yield potential in a changing climate.

Stomata, the gatekeepers of leaf gas exchange, regulate carbon dioxide uptake and water loss, functions increasingly critical as crops face more frequent, intense heat and drought. Under dry conditions, stomatal conductance (g s) typically decreases, limiting carbon assimilation and yield. Heat stress, in contrast, elicits variable g S responses: sometimes increasing to facilitate transpirational cooling, while at other times decreasing, especially when combined with drought. Heat and drought also induce complex, context-dependent shifts in stomatal anatomy. Smaller, denser stomata improve drought resilience in some cases, while reduced density confers greater tolerance in others. The optimal stomatal ideotype remains unknown, and different or even opposing traits may confer resilience dependent on the environmental scenario. Substantial genotypic variation in g s and stomatal anatomy, high heritability and co-localized quantitative trait loci for stomatal traits and yield highlight their untapped potential as breeding targets for climate-resilient crops. However, stomatal traits remain largely absent from breeding pipelines due to challenges of phenotyping at scale. This is changing rapidly. Advances in deep learning, porometry, digital microscopy, and remote sensing now enable high-throughput measurement of stomatal physiology and anatomy. Next-generation breeding technologies including clustered regularly interspaced short palindromic repeats (CRISPR), multi-omics approaches, and artificial intelligence-driven ideotype selection models could revolutionize breeding, allowing precise engineering of stomatal traits for resilience to environmental stress. The time has come to move beyond characterizing stomatal traits and start actively incorporating them into breeding strategies. By leveraging these technologies, stomatal traits can become high value targets, unlocking their potential to enhance crop performance in a hotter, drier future.

abiotic stress↗
PubMed2000

p53 knockout mice (-/-) are more susceptible than (+/-) or (+/+) mice to N-methyl-N-nitrosourea stomach carcinogenesis.

Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers. Mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this study we have investigated the susceptibility of p53 nullizygote (-/-), heterozygote (+/-) and wild-type (+/+) mice to N:-methyl-N:-nitrosourea (MNU) gastric carcinogenesis. p53 knockout mice were treated with 30 p.p.m. MNU in the drinking water 1 week on and 1 week off and killed after 5 weeks. The numbers of pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were 1.8, 1.7 and 22.6 in p53 (+/+), (+/-) and (-/-) mice, respectively. In a 15 week experiment, adenomas were found in 0 of 19 (+/+) (0%), 2 of 21 (+/-) (9.5%) and 6 of 10 (-/-) (60.0%) animals. Also, one well-differentiated adenocarcinoma was observed in a p53 (-/-) mouse. After 40 weeks treatment with 120 or 30 p.p.m. MNU there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/-) mice. However, mortality from carcinogen-induced lymphomas, leukemias and sarcomas was very much greater in the latter group. Homozygous knockout animals could not be maintained long term. PCR-single strand conformation polymorphism analysis of exons 5-8 of the p53 gene of DNA extracts from 68 gastric tumors consisting of 16 and 20 30 p.p.m. MNU-treated p53 (+/+) and (+/-) mice and 14 and 18 120 p.p.m. MNU-treated p53 (+/+) and (+/-) mice demonstrated no mutations. These results suggest that p53 may not be a direct target of MNU but rather play an important role as a gatekeeper in mouse stomach carcinogenesis induced by this direct acting agent.

Animals↗
PubMed2004

APC mutations in sporadic colorectal carcinomas from The Netherlands Cohort Study.

The adenomatous polyposis coli (APC) gene is considered to be a gatekeeper in colorectal tumourigenesis. Inactivating mutations in APC have been reported in 34-70% of sporadic colorectal cancer patients, the majority of which occur in the mutation cluster region (MCR). In this study, tumour tissue from 665 incident colorectal cancer patients, who originate from 120 852 men and women (55-69 years of age at baseline) participating in The Netherlands Cohort Study, was evaluated for the occurrence and type of APC mutations with regard to age at diagnosis, gender, family history of colorectal cancer, Dukes' stage, tumour differentiation and sub-localization. Mutation analysis of the MCR, which spans codons 1286-1513, was performed on archival adenocarcinoma samples using macrodissection, nested PCR and direct sequencing of purified PCR fragments. A large number of genetic aberrations (n = 978), including point mutations (n = 833), deletions (n = 126) and insertions (n = 19) was detected in the MCR in 72% of patients (479/665). In particular, we observed a large number of missense mutations, more than reported previously. This may indicate involvement in colorectal carcinogenesis, although their significance for APC functions is unclear. Truncating mutations were found in 37% of patients (248/665). Patients with rectosigmoid and rectum tumours relatively more frequently harboured C > T nonsense mutations and truncating frameshift mutations as compared with patients with proximal and distal colon tumours (P = 0.009 and P = 0.045, respectively). Differences in occurrence of truncating mutations with regard to tumour sub-localization suggest a different aetiology of tumourigenesis in colon and rectum.

Adenomatous Polyposis Coli Protein↗
PubMed2001

Internal market systems in Sweden: seven years after the Stockholm model.

BACKGROUND: Sweden, like other European countries in the 1990s introduced internal market reforms in the delivery of health care. Specifically, in Stockholm county, the Stockholm model was introduced to strengthen the position of patients in their choice of care. Other reform measures introduced included the family doctor's legislation, care guarantee and the adel reform. This paper reports interviews with Swedish physicians, politicians and health economists seven years after the introduction of these reforms. The broader goals of this paper are to explore the extent to which these changes have overtime affected the views of physicians as they reflect on their working conditions and experiences with the use of the diagnostic-related groups (DRG) system. METHODS: Data was obtained from in-depth interviews of 15 primary care physicians, 4 heads of hospital departments (surgery), 5 county council members and 4 health economists (N = 28). A content analysis was performed on major themes on the interview transcripts. RESULTS: The majority of our respondents reported that the financial incentives introduced through performance-based reimbursements do exist in Stockholm county and that productivity and efficiency have increased over the period of investigation. Primary physicians voiced support for the privatization process in health care delivery. Most physicians reported that they were generally satisfied with their work. Over half of the general physicians complained about their working conditions but felt they have a unique way to play as 'gatekeepers' in the overall Swedish health care delivery system. CONCLUSION: Our findings suggest that physicians are generally satisfied with their working conditions. Over 90% of our respondents support the use of a diagnostic-related group. What is clear though is that the primary care physician's role due to its potential benefit as an agent of cost control is important, but it is not clear that the primary care physicians have made a major contribution to the Swedish health care delivery system as they should be.

Attitude of Health Personnel↗
PubMed2005

Influence of local structural factors on physicians' sick-listing practice: a population-based study.

BACKGROUND: Physicians have a central role as gatekeepers to the social security system, including sick-listing. Variation in physicians' sick-listing practices has been demonstrated in several studies. The objective of this study was to determine whether local structural factors affect sick-listing practice. METHODS: A total of 57,563 consecutive sick-listing certificates, issued during 4 months in 1995 and 2 months in 1996, were collected from the local branches of the National Social Insurance Office in eight Swedish counties. County code, local community population size and presence of a hospital in the area were used as indicators of local structural factors. Length of the sick-listing certificates and of the sick-listing episodes were used as outcome variables. RESULTS: After adjustment for the influence of category of issuing physician, patients' age, sex and diagnosis ('case mix'), and type of certificate there was a large variation of the length of the sick-listing certificates and of the sick-listing episodes between counties, between communities of various size and between communities with or without a hospital in the area. All these factors were independently and significantly correlated to the length of the certificate and of the sick-listing episode. CONCLUSIONS: The results support the hypothesis that physicians' sick-listing practice is influenced by local structural factors.

Adolescent↗
PubMed2001

What prevents GPs from using outside resources for women experiencing depression? A New Zealand study.

BACKGROUND: GPs, often the 'gatekeepers' to mental health and related support services, have been found to refer on less often than seems desirable. OBJECTIVES: The aim of this study was to explore what issues GPs would discuss with, and which treatments and support services they would consider for, depressed women; and to investigate barriers to referrals to other resources. METHODS: All (217) GPs in one region of Auckland received questionnaires with a vignette and quantitative and qualitative questions concerning their responses to women experiencing depression. Twelve of the 86 respondents were interviewed. RESULTS: GPs wanted to know about a range of medical, psychological and social issues. The solutions valued were biological and psychological, with some also favouring social interventions, such as assistance with childcare. However, the GPs reported limited referrals to outside resources, and frequent use of medication, because of the high cost and limited availability of psychological treatment, and difficulties accessing practical help. CONCLUSIONS: This sample of GPs support improved accessibility, availability and affordability of psychological treatments and support services.

Depression↗
PubMed2001

A study of GP referrals to a family cancer clinic for breast/ovarian cancer.

OBJECTIVES: The aim of this study was to investigate the appropriateness of primary care referrals to the Oxford Regional Genetics Service on account of a family history of breast and/or ovarian cancer and to explore GPs' expectations following a referral. METHODS: Fifty consecutive GP referrers were sent a questionnaire post-referral, and their referral letters were reviewed. RESULTS: The study achieved a high response rate (94%) and showed that many GPs did not know which patients warrant referral to the genetics service and that they had unrealistic expectations of what happens at the clinic. CONCLUSIONS: If GPs are to fulfil their gatekeeper role effectively, and possibly become more involved in the delivery of genetic services in the future, it is clear that they require further education in this area.

Breast Neoplasms↗
PubMed2001

Guidelines for referral to a regional genetics service: GPs respond by referring more appropriate cases.

OBJECTIVES: The aim of this study was to see whether guidelines on whom to refer to a regional genetics service could improve the appropriateness of referrals to the service. It also aimed to assess whether the genetic clinic assessment of risk agreed with that described in the GP letter. METHODS: Referral guidelines were sent to all Oxfordshire GPs and the subsequent content of the referral letters was analysed. A retrospective assessment of referral letters sent during the 6 months before dissemination was also made. RESULTS: The study showed that post-guidelines, fewer "lower risk" referrals were made and that the description of the risk in the GP letter improved, so that a greater proportion of genetic clinic risks agreed with those described in the GP letter. CONCLUSION: The use of referral guidelines can help GPs to act as gatekeeper for referrals to secondary care.

Chi-Square Distribution↗
PubMed2001

Living with failing lungs: the doctor-patient relationship.

OBJECTIVE: The aim of the present study was to explore the perceptions and needs of chronic obstructive pulmonary disease (COPD) patients by a qualitative study using semi-structured interviews. METHODS: Sixteen patients with a diagnosis of COPD (age range 59-75 years) were recruited from two sample frames. One group were under the care of GPs and the second had received in-patient care previously at a district general hospital. Participants had either moderate or severe impairment of respiratory function identified by spirometric testing [forced expiratory volume in 1 second (FEV(1)) <50% of predicted value]. RESULTS: Primary and secondary care samples were chosen in the hope of identifying various aspects of care. However, the patients in this study primarily chose to discuss their relationship with their GP when considering aspects of their lives as a COPD patient. The most significant findings related to the respondents' chronic patient status, their ability to control symptoms and expectations of health care support. All these factors were connected to their perceived relationship with their GP. CONCLUSIONS: Doctors, as gatekeepers of health care resources, were seen to have immense power over the patients' lives. The need to be perceived in a good light by their doctor was intensified by their low self-esteem, poor control of symptoms and their chronic disease status. The majority of patients expressed a need to take a more active part in the decision-making processes involved in the management of their disease. A more balanced doctor-patient relationship could develop if frank and open discussions are based upon a shared decision-making approach.

Adaptation, Psychological↗