Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Gatekeeping”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 775 records · Page 43Linked to original sources
PubMed2006

Bach2 is involved in neuronal differentiation of N1E-115 neuroblastoma cells.

Bach1 and Bach2 are evolutionarily related members of the BTB-basic region leucine zipper transcription factor family. We found that Bach2 downregulates cell proliferation of N1E-115 cells and negatively affects their potential to differentiate. Nuclear localization of the cyclin-dependent kinase inhibitor p21 is known to arrest cell cycle progression, and cytoplasmic p21 has been shown to promote neuronal differentiation of N1E-115 cells. We found that ectopic Bach2 causes upregulation of p21 expression in the nucleus and in the cytoplasm in undifferentiated N1E-115 cells. In differentiated cells, Bach2 specifically triggers upregulation of cytoplasmic p21. Our data suggest that Bach2 expression could represent a switch during the process of neuronal differentiation. Bach2 is not expressed in neuronal precursor cells. It would have negative effects on proliferation and differentiation of these cells. In differentiated neuronal cells Bach2 expression is upregulated, which could allow Bach2 to function as a gatekeeper of the differentiated status.

Animals↗
PubMed1995

Dietary guidance workshop helps tribal program cooks make changes.

Nutrition educators need to view tribal program cooks as important food and nutrition gatekeepers for their clients, families, and communities. They need to train these cooks using a variety of educational techniques, including culturally sensitive food preparation sessions and classroom activities to increase cooks' knowledge and skills, enhance their self-esteem, and improve their attitudes about cooking more healthfully.

Adult↗
PubMed1997

Endothelial function as a determinant of vascular function and structure: a new therapeutic target.

Recent insights into the pathogenesis of vascular disease have opened up a new frontier that has implications for future therapies. The vasculature has been redefined as a vital organ that can regulate its own tone and structure via numerous cellular mechanisms. The endothelium plays the role of gatekeeper in this process, sensing and responding to stimuli and activating various vasoactive systems that function as mediators. Locally generated vasoactive substances such as angiotensin II and nitric oxide appear to be important determinants of vessel function and structure. Vasoactive substances generated within the endothelium influence cell proliferation and cell death in a complex interplay that, when disturbed, can result in structural alteration known as vascular remodeling. Normal vascular homeostasis is maintained by a balance between vasoconstrictors such as angiotensin II and vasodilators such as nitric oxide. Endothelial dysfunction involves an imbalance between vasoactive substances such that perturbations in the regulation of tone, hemostasis, and vessel structure result in the development of cardiovascular diseases, such as hypertension, atherosclerosis, and heart failure.

Animals↗
PubMed1998

Obstetrician-gynecologists as primary care physicians: the Oregon experience--early perceptions regarding the effects of legislative action.

OBJECTIVE: Our purpose was to assess whether legislative action influenced the role of obstetrician-gynecologists as primary care physicians. STUDY DESIGN: An observational study was performed on the basis of a questionnaire sent to 410 obstetrician-gynecologists and 27 medical directors of managed-care organizations. RESULTS: Of 67% of obstetrician-gynecologists and 96% of medical directors who responded, there was agreement as to the content of primary care, but a minority (38%) of obstetrician-gynecologists identified themselves as primary care providers. A minority of medical directors (35%) felt that obstetrician-gynecologists should serve in that role. Both obstetrician-gynecologists and medical directors felt that legislation had little impact. CONCLUSION: The reticence of obstetrician-gynecologists to assume a major role in primary care appears to be the result of an uneasiness with accepting a more comprehensive role in patient management and gatekeeping. They appear comfortable with the more traditional roles but feel that training and experience has not prepared them well for the management of more complex medical problems.

Female↗
PubMed2004

Enhanced stem cell survival in familial adenomatous polyposis.

Individuals with heterozygous germline adenomatous polyposis coli (APC) mutations or familial adenomatous polyposis (FAP) are born with normal appearing colons but later develop hundreds to thousands of polyps. Tumor progression apparently starts after somatic loss of the normal APC allele, but germline APC mutations may potentially alter niche stem cell survival through dominant-negative interactions or haploinsufficiency. Although morphologically occult, altered stem cell turnover or clonal evolution rates may be detected by measuring the diversity of crypt sequences, with greater diversity expected with longer lived stem cell lineages. Methylation pattern diversity (numbers of unique patterns per crypt) was higher in normal appearing crypts from four of five FAP colons compared to six non-FAP colons and one attenuated FAP colon. Simulations indicate higher FAP crypt diversity is consistent with slower clonal evolution from enhanced stem cell survival, either through increased stem cell numbers or decreased stem cell lineage extinction, which is predicted to increase progression rates to cancer. Enhanced stem cell survival was associated with APC mutations that remove some but not all catenin-binding repeats. Therefore, some APC mutations may be common in colorectal cancers because they confer occult pretumor "caretaker" and "gatekeeper" defects. FAP crypts accumulate more alterations from slower stem cell clonal evolution rather than increased error rates. In non-FAP crypts, enhanced stem cell survival conferred by somatic heterozygous APC mutations would favor fixation through occult clonal niche expansions. Heterozygous APC mutations may change stem cell survival during colorectal pretumor progression.

Adenomatous Polyposis Coli↗
PubMed2001

Evidence that furin is an authentic transforming growth factor-beta1-converting enzyme.

Transforming growth factor (TGF)-beta1 plays an essential role in cell growth and differentiation. It is also considered as a gatekeeper of immune homeostasis with gene disruption leading to autoimmune and inflammatory diseases. TGF-beta1 is produced as an inactive precursor polypeptide that can be efficiently secreted but correct proteolytic cleavage is an essential step for its activation. Assessment of the cleavage site has revealed a unique R-H-R-R sequence reminiscent of proprotein convertase (PC) recognition motifs and has previously demonstrated that this PC-like cleavage site is correctly cleaved by furin, a member of the PC family. Here we report that among PC members, furin more closely satisfies the requirements needed to fulfill the role of a genuine TGF-beta1 convertase. Even though six members of the PC family have the ability to cleave TGF-beta1, ectopic expression of alpha(1)-antitrypsin Portland (alpha(1)-AT-PDX), a potent furin inhibitor, blocked 80% of TGF-beta1 processing mediated by endogenous enzymes as demonstrated in an in vitro digestion assay. Genetic complementation of a furin-deficient LoVo cell line with the wild-type gene restores the production of mature and bioactivable TGF-beta1. Moreover, both furin and TGF-beta are coordinately expressed and regulated in vitro and in vivo in the hematopoietic and immune system, an important tissue target. These results demonstrate for the first time that furin is an authentic and adaptive TGF-beta1-converting enzyme whereas other members of the PC family might substitute or supplement furin activity. Our study advances our comprehension of the complexity of the TGF-beta system and should facilitate the development of therapeutically useful TGF-beta inhibitors.

Animals↗
PubMed2002

Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia.

A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently described in situ hybridization technique in archival samples (Meeker AK, Gage WR, Hicks JL, Simon I, Coffman JR, Platz EA, March GE, De Marzo AM: Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. American Journal of Pathology 2002, 160:1259-1268) for assessment of telomere length in tissue microarrays containing a variety of noninvasive pancreatic ductal lesions. These included 82 PanIN lesions of all histological grades (24 PanIN-1A, 23 PanIN-1B, 24 PanIN-2, and 11 PanIN-3) that were selected from pancreatectomy specimens for either adenocarcinoma or chronic pancreatitis. Telomere fluorescence intensities in PanIN lesions were compared with adjacent normal pancreatic ductal epithelium and acini (62 of 82 lesions, 76%), or with stromal fibroblasts and islets of Langerhans (20 of 82 lesions, 24%). Telomere signals were strikingly reduced in 79 (96%) of 82 PanINs compared to adjacent normal structures. Notably, even PanIN-1A, the earliest putative precursor lesion, demonstrated a dramatic reduction of telomere fluorescence intensity in 21 (91%) of 23 foci examined. In chronic pancreatitis, reduction of telomere signal was observed in all PanIN lesions, whereas atrophic and inflammatory ductal lesions retained normal telomere length. Telomere fluorescence intensity in PanIN lesions did not correlate with proliferation measured by quantitative Ki-67-labeling index or topoisomerase IIalpha expression. Thus, telomere shortening is by far the most common early genetic abnormality recognized to date in the progression model of pancreatic adenocarcinomas. Telomeres may be an essential gatekeeper for maintaining chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal epithelium. A critical shortening of telomere length in PanINs may predispose these noninvasive ductal lesions to accumulate progressive chromosomal abnormalities and to develop toward the stage of invasive carcinoma.

Carcinoma, Pancreatic Ductal↗
PubMed1990

Ten rules for reading clinical research reports.

This was not a scientific assessment of the scientific quality of the papers published by The American Journal of Surgery. It was an informal audit of the adequacy of the data analysis in the clinical research reports appearing in the 1987-1988 issues. As one who has devoted more than three decades to helping a great variety of people make sense of scientific data, I found the overall quality of data analysis in these papers to be above average for the medical literature; and yet, I found many instances of errors so serious as to render invalid the conclusions of the authors. My 10 proposed rules for reading clinical research reports constitute only an interim solution to a very worrisome problem. The real solution must come from the producers of and the gatekeepers for the medical literature.

General Surgery↗
PubMed1995

The role of the rehabilitation physician in the postacute continuum.

Compared to just 10 years ago, the US health care terrain looks much different today. In 1985, hospitals were the hub of a bustling delivery system that focused on acute care services and undervalued primary or preventive care. Health insurance benefits created incentives for consumers to use hospitals where their care was fully reimbursed, and discouraged office visits for which there were hefty copayments. Today, admissions into acute care hospitals are screened by none other than those same primary care physicians. These gatekeepers often have more authority over patient services and referrals than do the specialists and the hospitals. Financial incentives have made a 180 degrees shift, now motivating consumers to use outpatient care and office visits to satisfy the majority of their health care needs. Moreover, there are currently health care providers actively delivering a wide range of treatments and services that were not available or "covered" a decade ago. The migration of treatment out of hospitals into the vast frontier of postacute care has revolutionized our thinking about how patients receive treatment, in what locations, and by whom. This article describes the trends in financing and in clinical innovation that have contributed to the expansion of postacute alternatives. The factors that most clearly contribute to new opportunities facing rehabilitation physicians in postacute care are discussed, as are the added competencies required of those who choose to take a leadership role in the postacute delivery system. A case study of one model "managed care system" where the rehabilitation specialists are driving the care is presented. The future for rehabilitation specialists who are positioned to participate in setting the standards for high-quality postacute and chronic care in a future marketplace dominated by managed care is discussed.

Aged↗
PubMed1998

Assessing the knowledge of future internists and gynecologists in caring for a woman with tetraplegia.

OBJECTIVE: To assess the knowledge base and comfort level of potential physician "gatekeepers" when treating women with spinal cord injuries. Residents with at least 1 year of training in either internal medicine (IM) or obstetrics and gynecology (Ob/Gyn) from a large academic urban medical center were surveyed. STUDY DESIGN: This study used a written questionnaire that included a case scenario of a young woman with C6 tetraplegia who presented to her primary care physician for a routine visit. Information about the patient from her history and physical and laboratory exams was presented in stages, followed by open-ended queries to elicit information about the residents' problem-solving processes and management strategies. RESULTS: Thirty-eight percent (30 of 79) of the IM residents and 64% (14 of 22) of the Ob/Gyn residents completed the questionnaire. Significant deficits in knowledge about physical accessibility, spasticity management, and potential disability-related medical complications in pregnancy were found. More Ob/Gyn residents were aware of the risk of autonomic hyperreflexia than IM residents, whereas the IM residents demonstrated greater awareness of neurogenic bladder and skin problems. Both groups indicated they were not very comfortable in managing the patient's care. CONCLUSIONS: The results raise concern about the adequacy of the training of primary care physicians to meet the needs of people with severe disabilities.

Adult↗
PubMed1998

Mitochondrial control of apoptosis: the role of cytochrome c.

Mitochondrial cytochrome c (cyt c) has been found to have dual functions in controlling both cellular energetic metabolism and apoptosis. Through interaction with apoptotic protease activating factors (Apaf), cyt c can initiate the activation cascade of caspases once it is released into the cytosol. The loss of a component of the mitochondrial electron transport chain also triggers the generation of superoxide. Although cyt c can be released independent of the mitochondrial permeability transition (MPT), the accompanying cellular redox change can trigger the MPT. Since another apoptotic protease, AIF, is released by MPT, the two separate pathways provide redundancy that ensures effective execution of the cell death program. Anti-apoptotic Bcl-2 family proteins function as gatekeepers to prevent the release of both cyt c and AIF. In spite of their stabilization effect on the mitochondrial outer membrane, Bcl-2 proteins may also be involved in the direct binding of Apaf molecules as regulatory elements further downstream from the mitochondrial apoptotic signals.

Animals↗
PubMed2002

An essential role for REV3 in mammalian cell survival: absence of REV3 induces p53-independent embryonic death.

The REV3 gene of budding yeast encodes the catalytic subunit of DNA polymerase zeta that carries out translesion DNA synthesis. While REV3-null yeast mutants are viable and exhibit normal growth, Rev3-deficient mice die around midgestation of embryogenesis, which is accompanied by massive apoptosis of cells within the embryo proper. We have investigated whether REV3 is required for the survival of mouse cells and whether the embryonic lethality caused by REV3 deficiency can be rescued by introduction of a Rev3 transgene or by inactivation of p53, the cellular gatekeeper that regulates DNA damage-induced apoptosis. We show that Rev3(-/-) blastocysts were unable to survive and grow in culture but expression of a Rev3 transgene restored their outgrowth. Moreover, Rev3 transgene expression suppressed the apoptosis in E7.5 Rev3(-/-) embryos. The Rev3(-/-) embryonic lethality, however, was not rescued by either Rev3 transgene expression or p53 deficiency. These results reveal an essential role for REV3 in the survival and growth of mammalian cells and suggest that Rev3(-/-) embryonic death occurs in a p53-independent pathway.

Animals↗
PubMed2000

Diverse signalling by 5-hydroxytryptamine (5-HT) receptors.

Fourteen different receptor subtypes might be regarded as a diversity that is sufficient to accommodate the wide-ranging physiological roles of 5-hydroxytryptamine (5-HT). However, it is becoming clear that, for 5-HT as for other neurotransmitters, the concept of a receptor as a gatekeeper for a specific cellular process or event is too restrictive. Multiple receptor-mediated biochemical cascades can be activated in cells in response to an agonist by a number of mechanisms. Whereas it is well established that different agonists do not necessarily elicit the same magnitude of response, they probably also select between various possible signal transduction pathways. Receptor signalling may be diverse via a single receptor subtype as a consequence of specific agonist-receptor-G protein interactions. 5-HT receptors are even more heterogeneous when one considers that the amino acid sequence of these receptor subtypes may vary from individual to individual, and that there is an increasing number of receptor isoforms due to alternative splicing and RNA editing of 5-HT receptor transcripts. Activation, in particular constitutive, agonist-independent activation, of some of these receptor isoforms has been reported to be altered. This implies that ligands with similar binding affinities may display different pharmacological properties (partial agonist, antagonist, or inverse agonist) versus these receptor isoforms, depending on their activation state. Therefore, intervention with receptor ligands to modify hampered neurotransmission pathways is a difficult task, and one needs to consider the growing evidence of diversity in G protein-coupled receptor signalling.

Alternative Splicing↗
PubMed2005

Do physician attitudes and practices limit use of EUS in the staging and the treatment of esophageal carcinoma?

BACKGROUND: Although EUS provides superior local staging of esophageal carcinoma when compared with other tests, EUS seems to be underused by physicians. We designed this prospective study to determine whether EUS is ordered in the evaluation of esophageal cancer and whether staging information obtained would change management. METHODS: A total of 114 physicians were mailed a questionnaire that surveyed which tests are used in evaluating patients with esophageal cancer, the order in which they are requested, and their estimated cost. Physicians were asked to estimate prognosis and to indicate which therapy would be used for each specific TNM cancer stage. RESULTS: Of 114 physicians, 71 (62.3%) physicians from 4 disciplines responded. Only 47.3% of physicians would use EUS in the patient workup for esophageal cancer. Physicians would only order EUS after first obtaining an endoscopy, then a barium swallow, and then a CT scan ( p < 0.0001). A significantly greater number of internists (78.9%, p = 0.055) would not order EUS, and 31.6% of internists would not use any staging data before referral to another physician for definitive management. Physicians were accurate in their assessment of the prognosis for each cancer stage and the cost of each test. There was no difference in the use of surgery between disciplines for stages O, I, IIA, and IV. However, significantly more surgeons than nonsurgeons would use surgery for stage IIB (100.0% vs. 71.3%, p = 0.019), with a trend toward greater use by surgeons for stage III (64.3% vs. 34.1%, p = 0.11). Except for significantly greater use of chemotherapy by surgeons and oncologists for stage IIA than internists and gastroenterologists (36.6% vs. 3.1%, p = 0.0006), there were no differences between subspecialties with use of chemotherapy for all other stages or use of radiation therapy for any stage. CONCLUSIONS: Clinicians have an adequate understanding of patient survival based on cancer stage and a reasonable appreciation of cost for diagnostic tests regarding esophageal carcinoma. Specific data on cancer staging does impact treatment choices and management decisions. EUS is grossly underused by clinicians for staging esophageal cancer. Although internists may serve as gatekeepers, they fail to order EUS, order EUS only after less accurate tests, or fail to use staging data in management (especially referral) decisions. The ultimate modality of treatment may be more related to the type of physician that the patient is referred to, instead of the specific cancer stage. Education of primary care clinicians may be needed before the full impact of EUS on patient care can be appreciated.

Adenocarcinoma↗
PubMed1996

Insurance-related differences in the presentation of pediatric appendicitis.

In the pediatric population, there is strong evidence to suggest that a delay in treatment results in an increased risk of appendiceal perforation. However, it is not clear whether this delay arises from the parent seeking medical advice, the referring physician seeking surgical consultation, or the surgeon deciding to operate. To resolve this issue, the authors performed a retrospective chart review of all cases of confirmed acute appendicitis that presented to the pediatric surgical service of the Children's Hospital of Buffalo during a 4-year period (January 1990 through December 1993). All children (< or = 16 years of age) were categorized with respect to type of insurance coverage:Medicaid (or uninsured), health maintenance organization (HMO), or private fee-for-service. Their time until emergency room (ER) presentation, operating room (OR) presentation, and hospital discharge were recorded and compared. Their complications and perforation rates also were noted. Two hundred eighty-eight cases were reviewed. The rate of appendiceal perforation was significantly higher among the Medicaid patients (Medicaid, 44%; HMO, 27%; private, 23%; P < .05); their duration of symptoms before presentation was significantly longer (Medicaid, 47.3 +/- 4.1 hours; HMO, 29.3 +/- 1.9 hours; private, 23.1 +/- 2.5 hours; P < .01), and their hospital stay was longer (Medicaid, 7.9 +/- 0.9 days; HMO, 4.8 +/- 0.27 days; private, 4.6 +/- 0.44 days; P < .01). However, there were no significant differences in the time from presentation to the ER until definitive surgery in the OR. Children covered by Medicaid (or uninsured) presented later, had a higher risk of appendiceal perforation, and required a longer hospital stay. The parents of these children either failed to recognize the significance of their children's symptoms, or delayed seeking medical advice because of financial or logistical reasons. The gatekeeper consultation, required by the health maintenance organizations (HMO) did not result in a delay in presentation or have a negative impact on morbidity. Providing easier access to a primary care physician and improving parental health education/awareness may shorten the time until presentation for the uninsured/Medicaid patient.

Acute Disease↗
PubMed2000

Pancreatic cancer surveillance in a high-risk cohort. Is it worth the cost?

Pancreatic adenocarcinoma is the 10th most common malignancy and 4th largest cancer killer in adults. Earlier tumor detection through screening of high risk groups, presumably to increase the percentage of cases resectable for cure in these cohorts, has emerged as a prominent strategy to combat this disease. This article examines the feasibility of this strategy in patients with hereditary pancreatic cancer (HPC) and hereditary pancreatitis (HP). Because of a variety of factors, specific cost projections for screening with HPC kindreds are problematic at best. Patients with HP exhibit a 53-fold increased risk of pancreatic cancer, with a cumulative risk of 40% by age 70. The authors discuss the modalities available to screen this cohort and subsequently perform a theoretical cost analysis. The authors' findings suggest that screening has the potential to be cost-effective only in hereditary pancreatitis patients = 50 years-of-age. The most cost-effective option will likely combine an initial serologic test with high sensitivity and a subsequent serologic or pancreatic juice test with sufficient specificity to act as a "gatekeeper" to imaging with endoscopic ultrasound (EUS). Banking of blood and pancreatic juice samples should be mandatory in any screening protocol. The lower tumor yield in other high-risk groups (e.g., non-hereditary chronic pancreatitis) will effectively preclude the use of such screening protocols. The vast majority of patients will continue to present with unresectable disease.

Adenocarcinoma↗
PubMed1996

Home oxygen therapy.

Both the efficacy and the indications for LTOT have been well defined. Most of the studies performed have focused on patients with hypoxemia caused by COPD, and the benefits observed are assumed to apply to all patients with correctable hypoxemia. For Medicare patients, oxygen is reimbursed under a prospective payment system with all delivery systems considered to be cost and therapeutically equal. Because there are, in fact, substantial clinical differences in the medical indications for individual oxygen delivery systems, it is imperative that the prescribing physician be prepared to order the therapy that is most appropriate for each patient. Most home oxygen therapy is now being ordered by primary care physicians, often functioning as gatekeepers in managed care organizations. Education of primary care physicians in this area is often inadequate, and decisions for therapy should not be delegated to the equipment suppliers. If the study of home oxygen therapy conducted by the Office of the Inspector General were repeated today, less misuse of home oxygen would probably be found because of more clearly defined indications and requirements for therapy, but it is likely that the study would find that the level of knowledge of the prescribing physician has not maintained pace with the advances in technology. Continuing education for primary care physicians in this area of respiratory care is essential for appropriate medical management now and in the future.

Humans↗
PubMed2000

P53 null mice: damaging the hypothesis?

P53 is extremely well characterised as a tumour suppressor gene, and many activities have been attributed to it which are consistent with this function. However, despite being the subject of intense study it still remains unclear precisely which of these functions is crucial to its in vivo role as a tumour suppressor gene. This is particularly true of its role in the induction of apoptosis. The original observation of p53-dependent apoptosis gave rise to the following hypothesis: namely, that p53 deficiency leads to a persistence of DNA damaged cells which are the potential founders of malignancy. This review summarises the data for and against this hypothesis, with specific emphasis on data obtained from studies of the murine intestine. What emerges from these studies is a complex picture, where data can be obtained in support of this hypothesis, but there are many circumstances which exist where it is not supported. Taken together this collection of data suggests that the abrogation of p53-dependent apoptosis may indeed impact upon carcinogenesis and neoplastic progression, but that the simplistic notion of p53 as the single gatekeeper of this pathway is untenable.

Animals↗