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PubMed2002

Epithelial Ca(2+) channel (ECAC1) in autosomal dominant idiopathic hypercalciuria.

BACKGROUND: The epithelial Ca(2+) channel (ECaC) exhibits the defining properties for being the gatekeeper in 1,25-dihydroxyvitamin D(3)-regulated Ca(2+) (re)absorption. Its recently cloned human orthologue (ECaC1) could, therefore, represent a crucial molecule in human disorders related to Ca(2+)-wasting such as idiopathic hypercalciuria (IH). METHODS: Fifty-seven members of nine families with IH were investigated. Phenotyping was performed by measurements of urinary Ca(2+) excretion, while other underlying disorders were appropriately excluded. Initially, the recently suggested locus for kidney stone-associated hypercalciuria on chromosome 1q23.3-q24 was investigated. Next, direct mutation analysis of all 15 exons of the ECAC1 gene and 2.9 kb upstream from the start codon was performed. hECaC1, heterologously expressed in human embryonic kidney 293 cells, was characterized by patch-clamp analysis. RESULTS: The mode of inheritance in the studied pedigrees is consistent with an autosomal dominant trait. Haplotype analysis did not implicate a role of the locus on chromosome 1. The coding sequence of the ECAC1 gene was not different between the affected and the non-affected family members. In the 5'-flanking region, three single nucleotide polymorphisms were encountered, but these polymorphisms were observed regardless of the affection status of the screened family members. Patch-clamp analysis of hECaC1 was performed as the putative pore region contains four non-conserved amino acid substitutions compared with the other species. This analysis revealed the distinctive properties of ECaC, including a high Ca(2+) selectivity, inward rectification, and Ca(2+)-dependent inactivation. CONCLUSION: These results do not support a primary role for hECaC1 in IH in nine affected families. Because of the heterogeneity of the disease, however, the involvement of ECaC1 in other subtypes of IH cannot be excluded and needs further investigation. The electrophysiological properties of hECaC1 further substantiate its prime role in Ca(2+) (re)absorption.

Adolescent↗
PubMed2002

Improving the carboligase activity of benzoylformate decarboxylase from Pseudomonas putida by a combination of directed evolution and site-directed mutagenesis.

Benzoylformate decarboxylase (BFD) from Pseudomonas putida was subjected to directed molecular evolution to generate mutants with increased carboligase activity which is a side reaction of the enzyme. After a single round of random mutagenesis mutants were isolated which exhibited a 5-fold increased carboligase activity in aqueous buffer compared to the wild-type enzyme with a high enantiomeric excess of the product (S)-2-hydroxy-1-phenyl-propanone. From the same library, mutants with enhanced carboligase activity in water-miscible organic solvents have been isolated. The selected mutants have been characterized by sequencing, revealing that all mutants carry a mutation at Leu476, which is close to the active site but does not directly interact with the active center. BFD-L476Q has a 5-fold higher carboligase activity than the wild-type enzyme. L476 was subjected to saturation mutagenesis yielding eight different mutants with up to 5-fold increased carboligase activity. Surprisingly, all L476 mutants catalyze the formation of 2-hydroxy-1-phenyl-propanone with significantly higher enantioselectivity than the wild-type enzyme although enantioselectivity was not a selection parameter. Leu476 potentially plays the role of a gatekeeper of the active site of BFD, possibly by controlling the release of the product. The biocatalyst could be significantly improved for its side reaction, the C-C bond formation and for application under conditions that are not optimized in nature.

Amino Acid Substitution↗
PubMed1994

Relationship between sleep spindles and hypersomnia.

Sleep spindles (SS) and K complexes constitute the physiological markers of stage 2 sleep. Because sleep allows a spontaneous thalamic manifestation in the form of SS, one could hypothesize that there is some kind of relationship between SS and the complaint of hypersomnia. To investigate this possible relationship we compared nonhypersomnolent subjects with hypersomnolent patients who carried a diagnosis of narcolepsy or idiopathic hypersomnia. SS were counted in well-defined nocturnal stage 2 sleep segments, and the average SS density (number of SS in stage 2/minute stage 2) was tabulated for the entire night. Agreement between two independent scores was higher than 95%. The results show that the average SS density is higher in both cerebral hemispheres in the hypersomnolent group, especially in the idiopathic hypersomnia patients. At the beginning and at the end of the nocturnal sleep time, SS density is increased in this group compared with the normal one. These findings support the complaint of hypersomnia, mainly in idiopathic hypersomnia patients. This is in agreement with the notion that SS are generated by thalamic structures that serve a gatekeeping function during nonrapid eye movement sleep, and further suggests that their relative abundance expresses the power of that control.

Adolescent↗
PubMed2006

Comet fluorescence in situ hybridization analysis for oxidative stress-induced DNA damage in colon cancer relevant genes.

Our objective was to study whether products of oxidative stress, such as hydrogen peroxide (H(2)O(2)), trans-2-hexenal, and 4-hydroxy-2-nonenal (HNE), cause DNA damage in genes, relevant for human colon cancer. For this, total DNA damage was measured in primary human colon cells and colon adenoma cells (LT97) using the single-cell gel electrophoresis assay, known as "Comet Assay." APC, KRAS, and TP53 were marked in the comet images using fluorescence in situ hybridization (Comet FISH). The migration of APC, KRAS, or TP53 signals into the comet tails was quantified and compared to total DNA damage. All three substances were clearly genotoxic for APC, KRAS, and TP53 genes and total DNA in both types of cells. In primary colon cells, TP53 gene was more sensitive toward H(2)O(2), trans-2-hexenal, and HNE than total DNA was. In LT97 cells, the TP53 gene was more sensitive only toward trans-2-hexenal and HNE. APC and KRAS genes were more susceptible than total DNA to both lipid peroxidation products but only in primary colon cells. This suggests genotoxic effects of lipid peroxidation products in APC, KRAS, and TP53 genes. In LT97 cells, TP53 was more susceptible than APC and KRAS toward HNE. Based on the reported gatekeeper properties of TP53, which in colon adenoma is frequently altered to yield carcinoma, this implies that HNE is likely to contribute to cancer progression. This new experimental approach facilitates studies on effects of nutrition-related carcinogens in relevant target genes.

Adenomatous Polyposis Coli Protein↗
PubMed2003

Hypoxia causes down-regulation of 11 beta-hydroxysteroid dehydrogenase type 2 by induction of Egr-1.

Hypoxia causes several renal tubular dysfunctions, including abnormal handling of potassium and sodium and increased blood pressure. Therefore, we investigated the impact of hypoxia on 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) enzyme, a crucial prereceptor gatekeeper for renal glucocorticosteroid-mediated mineralocorticoid action. The effect of hypoxia was assessed in vitro by incubating LLC-PK1 cells with antimycin A, an inhibitor of mitochondrial oxidative phosphorylation. Antimycin A induced a dose- and time-dependent reduction of 11beta-HSD2 activity. The early growth response gene, Egr-1, a gene known to be stimulated by hypoxia was investigated because of a potential Egr-1 binding site in the promoter region of 11beta-HSD2. Antimycin A induced Egr-1 protein and Egr-1-regulated luciferase gene expression. This induction was prevented with the MAPKK inhibitor PD 98059. Overexpression of Egr-1 reduced endogenous 11beta-HSD2 activity in LLC-PK1 cells, indicating that MAPK ERK is involved in the regulation of 11beta-HSD2 in vitro. In vivo experiments in rats revealed that Egr-1 protein increases, whereas 11beta-HSD2 mRNA decreases, in kidney tissue after unilateral renal ischemia and in humans the renal activity of 11beta-HSD2 as assessed by the urinary ratio of (tetrahydrocortisol+5alpha-tetrahydrocortisol)/tetrahydrocortisone declined when volunteers were exposed to hypoxemia at high altitude up to 7000 m. Thus, hypoxia decreases 11beta-HSD2 transcription and activity by inducing Egr-1 in vivo and in vitro. This mechanism might account for enhanced renal sodium retention and hypertension associated with hypoxic conditions.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2004

The enigmatic protein kinase Cdelta: complex roles in cell proliferation and survival.

Protein kinase Cdelta (PKCdelta) has been implicated both as a tumor suppressor and a positive regulator of cell cycle progression. PKCdelta has also been reported to positively and negatively regulate apoptotic programs. This has led to conflicting hypotheses on the role of PKCdelta in the control of cell proliferation and survival. Surprisingly, PKCdelta mice develop normally and are fertile, indicating that PKCdelta is not critical for normal cell proliferation during development. However, PKCdelta may play important roles in neoplastic cell proliferation. In this review, we have summarized the apparent multifunctional properties of this enigmatic protein with regard to its role in the regulation of cell cycle progression and cell survival. It is proposed that PKCdelta has both tumor suppressor and proliferation capabilities that can be recruited as a backup kinase for both gatekeeper tumor suppression and as an activator of the Ras/Raf/MEK/MAP kinase signaling pathway in cell proliferation.

Animals↗
PubMed2001

Syringocystadenoma papilliferum: a study of potential tumor suppressor genes.

Syringocystadenoma papilliferum (SP) is a benign tumor most commonly located on the scalp or face, which frequently arises from a nevus sebaceus (NS). Transition of SP to basal cell carcinoma (BCC) and, albeit rarely, to metastatic adenocarcinoma may occur. Allelic deletions of the human homologue of the drosophila patched gene (PTCH) occur in both NS and BCC. To search for genetic changes in SP, a microdissection-based genetic analysis using polymorphic markers at 9q22 (PTCH; D9S15, D9S303, D9S287, D9S252) as well as markers at 9p21 flanking the tumor suppressor gene p16 (IFNA, D9S171) was performed. Glandular epithelium consisting of two rows of cells as well as adjacent normal tissue or inflammatory infiltrates in the stroma, when present, was dissected and subjected to single-step DNA extraction and loss of heterozygosity (LOH) analysis. Two of 10 informative SP cases showed LOH at 9q22 (PTCH). Three of 7 informative SP cases showed allelic deletions at 9p21 (p16). Allelic loss at 9q22 is consistent with the clinical observation of transition of SP to BCC. The finding of frequent allelic loss at 9p21 is unlikely to be related to the rare transition of SP to metastatic adenocarcinoma. Our study supports the hypothesis of a gatekeeper role of the tumor suppressor gene p16 in a variety of benign and malignant tumors, including SP.

Adenocarcinoma, Papillary↗
PubMed2002

Abetalipoproteinemia-like lipid profile and acanthocytosis in a young woman with anorexia nervosa.

We report the case of a 17-year-old woman with anorexia nervosa (AN) who developed an abetalipoproteinemia-like lipid profile and acanthocytosis. These abnormalities resolved slowly as her nutritional status improved. We considered 3 possible causes of an abetalipoproteinemia-like lipid profile in AN: (1) depletion of hepatic substrate for apolipoprotein B synthesis, (2) lack of exogenous fatty acids with exhaustion of endogenous stores of triglycerides in adipose tissue, and (3) preservation of the lipoprotein lipase (LPL) mass. This unusual case provides important clues that enhance our understanding of lipid metabolism under exogenous and endogenous fat deprivation and highlights the pivotal role of LPL as a gatekeeper of the energy source.

Abetalipoproteinemia↗
PubMed1999

Analysis of workforce, distribution of care, and practice preference in pediatric plastic surgery.

To determine the future needs in manpower for pediatric care as it relates to pediatric specialists, a study was conducted by the American Academy of Pediatrics to see the needs of manpower that will provide access of pediatric care to all. A pediatric plastic surgery survey was set in the form of a list of questions that was mailed to the respective societies with pediatric plastic surgeons as members. The survey was reviewed, and the results were studied. The outcome is presented in the form of findings related to the overall practice of plastic surgery. Based on the percentage of pediatric care that is provided, there were two types of pediatric plastic surgeons. Those with the high percentage of pediatric care tend to stay near health science centers; however, both groups tend to spend time (each to a different extent) tending to other plastic surgery problems. Today we have adequate access to care in the health system for pediatric plastic surgery problems despite the shift in the health care environment. Managed care continues to use the pediatrician as a "gatekeeper" in determining the overall access for patients with problems related to pediatric plastic surgery.

Canada↗
PubMed1987

Survey of attitudes among three specialties in a teaching hospital toward alcoholics.

Although physicians are typically "gatekeepers" for the diagnosis and treatment of alcoholism, a lack of specific alcoholism training and negative attitudes toward alcoholics can establish formidable barriers to recognition and treatment of the condition. In the study reported here, the authors examined differences in attitudes toward and knowledge and treatment of alcoholism among physicians in three specialties. A questionnaire pertaining to alcoholism and alcoholics was mailed to 385 internists, surgeons, and psychiatrists at a teaching hospital. Half received a version concerning male alcoholics, and half received one concerning female alcoholics; the versions were identical except for the gender of the alcoholic referred to in the questionnaire. Fifty-three percent returned the questionnaire, and their responses showed that these physicians viewed male and female alcoholics similarly. Overall, the respondents considered them treatable but maintained negative perceptions of their personalities. The psychiatrists held the most positive views of the treatability of alcoholism and the most negative views of alcoholics' personalities, whereas the surgeons held the most positive views of alcoholics' personalities and the most negative views of treatability. The internists, surgeons, and psychiatrists reported significant differences in the adequacy of their education on alcoholism, in their methods of handling alcoholics, and in their desire to learn about alcoholism. These findings are discussed in terms of continuing education in alcoholism treatment for physicians.

Alcoholism↗
PubMed1991

An academic medical center's experience with mandatory managed care for Medicaid recipients.

This paper reports on The Hospital of the University of Pennsylvania's experience and concerns as a participating primary care site in a Medicaid managed care program (HealthPASS), which was established in 1986. Enrollment is mandatory for approximately half of Philadelphia's medical assistance population. Participating primary care sites receive monthly capitation for enrollees and serve as "gatekeepers" for specialty and inpatient services. The report discusses why the academic medical center chose to participate in the program and how existing activities were modified to meet both increased demand for primary care and increased administrative requirements. It also identifies characteristics of the HealthPASS program and of the medical center that have impeded effective case management of care for the urban poor population that the program serves. Improving the quality of care for the medically indigent while controlling costs is essential, but political realities and the special needs of the Medicaid population must be acknowledged. Increased attention must be given to the impact that political compromises have on the design and effectiveness of a managed care program.

Academic Medical Centers↗
PubMed1998

Educating future physicians for Ontario.

In 1987, Ontario's physicians conducted a strike, ultimately not successful, over the issue of "extra billing." The fact that the Ontario public did not support this action reflected a major gap between the profession's view of itself and the public's view of the profession. In 1990, the province's five medical schools launched a collaborative project to determine more specifically what the people of Ontario expect of their physicians, and how the programs that prepare future physicians should be changed in response. The authors report on the first five years of that ongoing project. Consumer groups were asked to state their views concerning the current roles of physicians, future trends that would affect these roles, changes in roles they wished to see, and suggestions for changes in medical education. Methods used included focus groups, key informant interviews, an extensive literature review, and surveys, including a survey of health professionals. Concurrently, inter-university working groups prepared tools and strategies for strengthening faculty development, assessing student performance, and preparing future leadership for Ontario's medical education system. Eight specific physician roles were identified: medical expert, communicator, collaborator, health advocate, learner, manager ("gatekeeper"), scholar, and "physician as person." Educational strategies to help medical students learn to assume these eight roles were then incorporated into the curricula of the five participating medical schools. The authors conclude that the project shows that it is feasible to learn specifically what society expects of its physicians, to integrate this knowledge into the process of medical education reform, and to implement major curriculum changes through a collaborative, multi-institutional consortium within a single geopolitical jurisdiction.

Consumer Behavior↗
PubMed2000

Three strategies used by academic health centers to expand primary care capacity.

The growth of managed care in the late 1980s and early 1990s severely disadvantaged academic health centers (AHCs). The reliance on primary care gatekeeping and selective contracting by managed care plans were two contributing factors. Because most AHCs had only a modest primary care capacity, they were understandably concerned about their strategic positions. Thus, many felt it was essential to expand their primary care capacities to ensure downstream referrals, to improve contract negotiations with third parties, and to permit assumption of risk for defined populations. Among the different approaches used, three principal strategies emerged for the expansion of the primary care capacity of AHCs: (1) the "assembly strategy," in which many AHCs recruited new generalist faculty into existing clinical departments; (2) the "acquisition strategy," in which AHCs purchased established primary care practices in the community; and (3) the "affiliation strategy," in which some AHCs affiliated with primary care physicians in the community and formed networks of academic and community physicians. For each of these approaches, the author reviews the relative merits and disadvantages, and analyzes why some AHCs' original assumptions about the imperative for increasing primary care capacity may have been spurious. He concludes that recent marketplace and regulatory changes may make it less necessary for AHCs to secure substantial primary care bases in the future.

Academic Medical Centers↗
PubMed1997

Looking down the prospectoscope: obstetrics/gynecology in the year 2000 and beyond.

It should be emphasized that the American College of Obstetricians and Gynecologists is advocating that those Obstetrician/Gynecologists who wish to be included under this new designation primary care physician "provide only ambulatory primary care," states the Executive Director, Dr. Ralph W. Hale. Thus, we enter a new era and must understand the lexicons, including HMO, independent provider organization, PPO, managed care organization, exclusive provider organization, IPA, hospital-physician organization, health plan provider data and information set, physician-hospital organization and utilization management--all these have become words with increased meaning for all clinicians. It is a rare physician lounge without physicians preoccupied by discussions regarding managed care, "Have you heard the latest reimbursement schedule?" or "It's less than Medicaid," and the discussions continue indefinitely. There has been a continued effort to have physicians be cost-efficient in their approach to all aspects of obstetrical and gynecological care. Capitation has proven to be the virtually exclusive method of reimbursement. Continued care with respect to clinical outcome, resource utilization, patient satisfaction, and quality care restructuring of practice/personnel/patient approach is based on the quarterly patient surveys, which have been evaluated and carefully reviewed. Patient satisfaction with a sincere effort to provide quality of care remains the underlying theme with respect to obstetrical and gynecological patient care. These are basic tenets. What is the future of obstetrics/gynecology with respect to managed health care? It does make sense to have a planned and well-coordinated approach to delivery of obstetrical as well as gynecological care with the goal of "quality" delivered at a "lower cost" having an overall positive impact on OB/GYN health care delivery. Currently, there are a number of states which have specific legislation enabling a patient to proceed to secure gynecological without going through a "gatekeeper." As we approach the year 2000 and beyond, clearly the prediction is that this will be an ever-increasing goal and objective of state medical societies to provide easy access for women's health care. Thus, we have awakened into a new era that is hallmarked by efficient, quality medical care provided by a physician who initially trained to be a subspecialist and now is an ambulatory primary care physician.

Cost-Benefit Analysis↗
PubMed2000

Ethical responsibilities of editors, reviewers, and authors.

Scientific misconduct, which is neither new nor unique, is prevalent in the medical literature. Although fabrication of data obviously is unethical, and although ethical rules of conduct for certain aspects of medical studies, such as informed consent, are theoretically accepted worldwide, numerous authors do not adhere to ethical rules of conduct. Ethically, the editor is responsible, as a gatekeeper, for ensuring that material to be published is accurate and valid. Thus, the editor's main responsibility is to the reader. Nonetheless, the editor also must serve the author by selecting unbiased reviewers and by providing the assurance that material will be selected for publication based solely on the scientific quality of the material. Peer reviewers are obligated to maintain a posture of confidentiality throughout the review process. Authors are responsible for adequate planning before undertaking a study, and for safeguarding patients' rights during the study. The author must read all cited references completely, strive for accuracy, and be certain that the material reported is valid, because it will be used in the treatment of patients. Hopefully, awareness of the ethical problems related to medical writing will provide a clearer understanding of the ethical aspects of medical writing.

Authorship↗
PubMedDate not supplied

Strategies to increase patient control of visiting.

Controlling patient visiting commonly evokes ambivalent feelings among critical care nurses. Much has been written about the needs of the family and benefits of social support as well as about the nurses' opinions about visitors. Nurses have traditionally been advocates for their patients. Critical care nurses, in particular, have felt a special duty to control the environment and be a "gatekeeper." In an effort to "protect" the patient, perhaps nurses and families have neglected to consult the one person who really should have the last word on visiting-the patient!

Attitude of Health Personnel↗
PubMed2001

Admissibility of scientific evidence post-Daubert.

Proof of medical causation is the key element in cases involving alleged radiation injury. Until 1993, the use of scientific testimony in the courtroom was governed by the Frye doctrine requiring that a theory be "generally accepted" before it can be the basis of an expert's opinion. Applying that rule trial courts adopted a "let it all in" approach resulting in a near overdose of pseudoscience presented to juries. With its decision in Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 113 S. Ct. 2786 (1993), the U.S. Supreme Court announced a new five-factor, non-exclusive test for federal district courts to consider when assessing the opinion of scientific experts. The Court further directed that the trial courts, acting as a gatekeeper for expert evidence, must evaluate whether there is an adequate "fit" between the expert's data and the opinion offered. This article examines how the Daubert standard has been implemented in federal court to combat junk science. Examples from recent case law dealing with operational health physics issues are presented as an illustration of the use of the five-factor test to challenge questionable testimony on causation. Guidance is offered to prospective expert witnesses in radiation-related litigation to insure that proposed testimony will be admissible in district court.

Causality↗
PubMed1994

Ambulatory surgery marketing to primary care physicians.

The leaders of health care organizations across the country are facing significant pressure to improve the quality of their services, reduce operating costs, and adjust to decreases in reimbursement. Survival of a surgery center is achieved when physicians work together to decrease their vulnerability to outside forces and increase their ability to reach desired objectives. Improved communication, operational efficiency, and cost effectiveness are the strategic imperatives. As competition for patient referrals increases among providers, in the midst of a national trend, a surgery center marketing program must be well organized and carefully designed to meet the needs of all its customers. A surgery center that can strategically place itself as a critical link between the surgical specialist and the gatekeeper will survive and prosper in the current health care world.

Ambulatory Surgical Procedures↗