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PubMedDate not supplied

New concepts in health care: some preliminary ideas.

Health care discussions in many countries tend to focus on cost containment without taking into account the problem of quality of care. The starting point for our ideas is the description of quality as the optimal relation between care demander and care provider. The difficulties in assessing quality of care are outlined. The question remains which health care model offers the best opportunities to have both high quality care and affordable costs. A proposal is made for a model in which the care demander and care provider, i.e. the client and physician, are natural allies. A special role is fulfilled by the family physician: a key role, as case manager, as gatekeeper. Special attention should be directed towards the financial consequences. It is proposed that small-scale experiments should be started to evaluate the model advanced in the text.

Cost Control↗
PubMedDate not supplied

NHS direct: managing demand for primary care?

This paper considers how NHS Direct is affecting demand for primary care in particular out-of-hours services from GPs. This is reviewed through a 3-year study of NHS Direct and HARMONI, the integrated telephone health helpline based in West London. It describes the policy background and development of the services on the site, and some of the outcomes of the HARMONI commissioned research to answer the question 'Has NHS Direct increased the workload for HARMONI doctors?'. The research adopted both a qualitative and quantitative approach using cross-sectional and longitudinal analysis of the data collected. The analysis of the data reveals the issues as both complex and dynamic in nature. The research shows that while there has been no significant change to the total volume of activity, changes within patient groups notably the elderly and children, and in individual GP practices may be significant. In addition, the changes in organizational arrangements may influence significant changes in referral patterns such as GP out-of-hours visits. This was confirmed in the interview data indicating a link between the change in nurses' role from gatekeeper to patient advocate, which happened when they ceased to be employees of the part-time co-op and began to work instead for the 24 hours, 7 days a week NHS Direct service. The conclusions drawn are that behavioural and organizational changes are at least as significant as the evidence-based computerized decision support software in changing the demand for primary care. Further evidence cited is that a different demand pattern of calls was experienced by those local GPs not integrated into out-of-hours provision at NHS Direct West London at the time of the study.

After-Hours Care↗
PubMedDate not supplied

Organization and delivery of primary health care services in Petrópolis, Brazil.

The objective of the study was to adapt and apply an instrument to measure the organizational features of the primary care system in the municipality of Petrópolis. The study compared the performance of the new Family Health Program (Programa Saúde da Família or PSF) with traditional primary care facilities using data from facility surveys and key informant interviews. The main results include: (a) the methodology was capable of distinguishing between the two types of primary care services in the municipality; (b) the PSF clinics scored higher on most dimensions of primary care, although in some areas the traditional health units had equivalent scores; and (c) data obtained from interviewing key informants was generally compatible with that obtained by conducting facility surveys. The results suggests that in spite of making important advances in primary care, the municipality of Petrópolis continues to face several challenges including the need to improve access, enforce the gatekeeper role of primary care, and improve the coordination and community orientation of both types of primary care services. The methodology could be used to set objectives and monitor progress towards improving the organization and delivery of primary care in Petrópolis and elsewhere.

Brazil↗
PubMed2006

Comprehensive analysis of the p53 status in mucosal and cutaneous melanomas.

The abrogation of the function of the "gatekeeper of the genome", p53, is the most prevalent molecular alteration in solid human tumors. Regarding melanomas the involvement of p53 alterations is discussed controversially to date. In order to evaluate the status of p53 in detail, primary tumors and metastases of 63 sporadic cutaneous (CM) and mucosal (MuM) melanomas were examined by immunohistochemistry and sequence analysis of the entire coding region of the p53 transcript, i.e., exons 2 to 11. In addition, loss of heterozygosity (LOH) and loss of allele-specific transcription (LOT) were determined. Accumulation of the p53 protein occurred in most of the CM and MuM specimens (71% and 58%, respectively). In contrast, protein stabilizing p53 mutations were observed in 14% of the CM and no mutation was found in MuM specimens. Two of the aberrations located outside the core domain. LOH was detected in 22% CM and 58% MuM, and LOT in 25% of the CM specimens. The genotype distribution at the polymorphic p53 codon 72 in melanoma patients differed significantly from control subjects. The calculation of odds ratios (OR) and 95% confidence intervals (CI) indicated an increased risk for developing cutaneous melanomas in individuals carrying the Pro-coding allele. Altogether, aberrant p53 expression appears to be a common event in both CM and MuM.

Aged↗
PubMed2004

Incorporating pathologists' criteria of malignancy into the evolutionary model for cancer development.

A wide variety of alterations in cell and tissue structure still form the basis for cancer diagnosis by pathologists. Cancer development is recognized to be an evolutionary process [Foulds, 1954; Cairns, 1975; Nowell, 1976; Sager, 1982; Tomlinson et al., 1996; Cahill et al., 1999; Tomlinson and Bodmer, 1999], but the phenotypic changes diagnostic of cancer (pathologists' "criteria of malignancy") have not been integrated into the existing evolutionary framework. Since phenotypic changes bear an important relationship to the genetic and physiologic changes underlying Darwinian evolution, we propose that diagnostic structural alterations also bear an important and predictable relation to both the cancer genes and the functional alterations active at any particular step in the development of a cancer. Cancer genes are predicted to mediate the acquisition of cellular-level diagnostic criteria and the diagnostic cellular-level structural changes should reflect in a useful manner the altered cell physiology required for the cell to achieve increased "cellular fitness" at any particular step of colonal evolution. Tissue-level criteria of malignancy should relate less directly to specific cancer genes, but tissue-level criteria should still provide essential insight into the interplay of the altered cellular fitness with the constraints imposed by the cells' microenvironment. The evolutionary framework allows tissue-level criteria of malignancy to be expressed in terms of viable hypotheses for the mechanism of clonal expansion at any particular step in cancer development. This approach to conveying the tissue-level criteria of malignancy complements pattern recognition approaches to diagnosis, and establishes common ground between pathology and cell biology. When viewed from this perspective, the functions of cancer genes appear quite different from those predicted by the "Gatekeeper, Caretaker" or "Hallmarks of Cancer" models. Finally, a full evolutionary framework incorporating the criteria of malignancy restores congruity between the histogenetic classification and the emerging molecular classification of cancer.

Cell Transformation, Neoplastic↗
PubMed1994

Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone.

The bone replacement process in the adult skeleton is known as remodeling. When bone is removed by osteoclasts, new bone is laid down by osteoblasts in the same place, because the load bearing requirement is unchanged. Bone is usually replaced because it is too old to carry out its function, which is mainly mechanical in cortical bone and mainly support for homeostasis and hematopoiesis in cancellous bone. Remodeling always begins on a quiescent bone surface, separated from the marrow by flat lining cells that are one of the two modes of terminal differentiation of osteoblasts. Lining cells are gatekeepers, able to be informed of the need for remodeling, and to either execute or mediate all four components of its activation-selection and preparation of the site, recruitment of mononuclear preosteoclasts, budding of new capillaries, and attraction of preosteoclasts to the chosen site where they fuse into multinucleated osteoclasts. In cortical bone, osteonal remodeling is carried out by a complex and unique structure, the basic multicellular unit (BMU) that comprises a cutting cone of osteoclasts in front, a closing cone lined by osteoblasts following behind, and connective tissue, blood vessels and nerves filling the cavity. The BMU maintains its size, shape and internal organization for many months as it travels through bone in a controlled direction. Individual osteoclast nuclei are short-lived, turning over about 8% per d, replaced by new preosteoclasts that originated in the bone marrow and travel in the circulation to the site of resorption. Refilling of bone at each successive cross-sectional location is accomplished by a team of osteoblasts, probably originating from precursors within the local connective tissue, all assembled within a narrow window of time, at the right location, and in the right orientation to the surface. Each osteoblast team forms bone most rapidly at its onset and slows down progressively. Some of the osteoblasts are buried as osteocytes, some die, and the remainder gradually assume the shape of lining cells. Cancellous bone is more accessible to study than cortical bone, but is geometrically complex. Although remodeling conforms to the same sequence of surface activation, resorption and formation, its three-dimensional organization is difficult to visualize from two-dimensional histologic sections.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2002

The random development of LOH on chromosome 9q in superficial bladder cancers.

Allelic loss on chromosome 9q is a very frequent event in bladder carcinogenesis. In recent years, efforts have been directed towards identifying the postulated tumour suppressor genes on this chromosome arm by deletion mapping and mutation analysis. However, no convincing candidate genes have been identified. This paper describes the development of chromosome 9q alterations in multiple recurrent superficial bladder cancers of ten patients and shows that loss of heterozygosity (LOH) on this chromosome is almost never the characteristic first step. The regions of loss are multiple and variable in different tumours from the same patient and expand in subsequent tumours. Moreover, the regions of loss vary from patient to patient. It is concluded that even if 9q harbours a bladder cancer gatekeeper gene, it is unlikely that the gene will be identified through LOH analysis alone.

Chromosomes, Human, Pair 9↗
PubMed2006

Proteome profile changes that are differentially regulated by lipid and protein phosphatase activities of tumor suppressor PTEN in PTEN-expressing U-87 MG human glioblastoma cells.

The phosphatase and tensin homolog tumor suppressor (PTEN) belongs to a class of "gatekeeper" tumor suppressors together with p53, retinoblastoma and adenomatous polyposis. It is considered one of the most important tumor suppressors in the post p53 era. Previously to identify the molecules involved in the signaling network regulated by PTEN using proteomic tools, we reported global proteome profiles at different time points using the PTEN inducible NIH3T3 cells (Kim, S.-y., Kim, Y. S., Bahk, Y. Y., Mol. Cells 2003, 15, 396-405). However, the system had a critical limitation that NIH3T3 cell has endogenous wild-type PTEN and, thus to be exact, the induced PTEN could not give the answer about the real physiological roles of this tumor suppressor. Here, to find out PTEN-related protein network we have established various PTEN (wild-type, an activity inert C124G, and a lipid phosphatase deficient G129E)-expressing cell clones in U-87 MG human glioblastoma cells lacking detectable PTEN as a result of genetic lesions. In this biological context, we compared their morphological and expression patterns, and proteome images of each PTEN-expressing cell clone by 2-DE followed by identification with MALDI-TOF MS. We obtained some pieces of evidence that morphological change by PTEN expression is mediated by its protein phosphatase activity and their growth rate by the lipid phosphatase activity. The proteomic approaches showed that 30 proteins possibly correlated with PTEN's protein phosphatase activity (13 down-regulated and 17 up-regulated) and 20 with the lipid phosphatase activity (14 down-regulated and 6 up-regulated) were identified. Taken together, we conclude that the comparative analysis of proteome from various PTEN-expressing cells has yielded interpretable data to elucidate the protein network directly and/or indirectly caused by individual phosphatase activities of PTEN in vivo.

Blotting, Western↗
PubMed2006

Molecular dynamics study of amyloid formation of two Abl-SH3 domain peptides.

Molecular dynamics (MD) simulations were carried out for two-strand and ten-strand beta-sheets constructed from two peptides corresponding to the diverging turn of two homologous Abl-SH3 domains, DLSFMKGE (MK; from Drosophila) and DLSFKKGE (KK; from man), in explicit water at the temperatures of 30, 170/190 and 300 K. It was found that the 2 x MK beta-sheet is more stable than the 2 x KK beta-sheet, and that the 10 x MK beta-sheet is more stable than the 10 x KK beta-sheet; this suggests that the MK systems are fibril-creating and the KK systems are not. These results might explain why most SH3 domains possess two conserved basic residues at the diverging turn, which may act as gatekeepers in order to avoid aggregation.

Amino Acid Sequence↗
PubMed1997

Food and general neophobia and their relationship with self-reported food choice: familial resemblance in Swedish families with children of ages 7-17 years.

The aims were to study food and general neophobia in Swedish families, age and gender differences and familial resemblance. Also, the relationships between the level of food neophobia of individual family members and earlier experience with and the likelihood of future tasting of specific foods were investigated. A group of randomly selected families (nation-wide, stratified, N=1593) with children age 7-17 years were invited and 722 participated. The results are based on the Food and General Neophobia Scales and an ad hoc Food Frequency Questionnaire. The overall levels of food and general neophobia were low. Fathers showed significantly higher total food neophobia scores than did the mothers, and children were significantly more neophobic than their parents. The younger children had higher food and general neophobia scores than the older children. Nine-year-old boys had higher food neophobia scores than 9-year-old girls. Some evidence was found for familial resemblance with respect to both food and general neophobia. Gatekeepers' (the person who takes the greatest responsibility for food purchase and preparation) self-reported serving of the foods and mothers', fathers' and children's self-reported consumption of foods were correlated with their respective levels of food neophobia. The strongly neophobic subjects in all groups of family members were less likely to have eaten the listed foods than were the less neophobic. Thus, food neophobia seems to be related to everyday food choice.

Adolescent↗
PubMedDate not supplied

Iron overload in mice expressing HFE exclusively in the intestinal villi provides evidence that HFE regulates a functional cross-talk between crypt and villi enterocytes.

Hereditary hemochromatosis (HH), a common autosomal recessive disorder due to a mutation in HFE, which encodes an atypical MHC class I glycoprotein, is characterized by excessive absorption of dietary iron. Little is known however of the apparently complex pathophysiology of HFE involvement in the process of iron influx. Here, in order to tackle the issue in vivo, we decided to target HFE expression exclusively to the relevant tissue, intestinal epithelium. This was achieved by putting HFE under transcriptional control of the rat fatty acid binding protein (Fabpi) promoter. Quite unexpectedly, Fabpi-HFE mice had significantly elevated serum transferrin saturation levels in comparison to those of normal littermates. By a careful, layer by layer analysis of transgene expression along the crypt-villus axis, we were able to affirm that the ectopic expression of transgenic HFE in the differentiated villi enterocytes was responsible for ferric hyperabsorption, a phenomenon exacerbated in the absence of endogenous HFE expression, which we assessed by crossing the transgene onto an HFE(-/-) (knockout) background. This forced dichotomy between the absence of HFE in the crypt and expression in the villi provides experimental support that HFE functions as a "gatekeeper," regulating the cross-talk between the crypt and villi enterocytes and thereby modulating the avidity of mature enterocytes for dietary iron.

Animals↗
PubMed2000

Molecular cloning, tissue distribution, and chromosomal mapping of the human epithelial Ca2+ channel (ECAC1).

Functional and morphological analyses indicated that the epithelial Ca2+ channel (ECaC), which was recently cloned from rabbit kidney, exhibits the defining properties for being the gatekeeper in transcellular Ca2+ (re)absorption. Its human homologue provides, therefore, a molecular basis for achieving a better understanding of Ca2+ mal(re)absorption. By applying the RACE technique, the full-length cDNA of human ECaC (HGMW-approved symbol ECAC1) was obtained. It consisted of 2,772 bp with an open reading frame of 2,187 bp encoding a protein of 729 amino acids with a predicted molecular mass of 83 kDa. Phylogenetic analysis indicated that this highly selective Ca2+ channel exhibits a low level of homology (<30%) to other Ca2+ channels, suggesting that it belongs to a new family. hECaC was highly expressed in kidney, small intestine, and pancreas, and less intense expression was detected in testis, prostate, placenta, brain, colon, and rectum. These ECaC-positive tissues also expressed the 1,25-dihydroxyvitamin D3-sensitive calcium-binding proteins, calbindin-D9K and/or calbindin-D28K. The human ECaC gene mapped to chromosome 7q31.1-q31.2. Taken together, the conspicuous colocalization of hECaC and calbindins in organs that are not prime regulators of plasma Ca2+ levels could illustrate new pathways in cellular Ca2+ homeostasis.

Amino Acid Sequence↗
PubMed1993

Coping with distress and self harm: the impact of a primary prevention program among adolescents.

The effectiveness of a school-based primary prevention psychological program is assessed in the present study. The program was designed to (a) improve students' distress-coping, (b) prepare them as "gatekeepers" with regard to self-destructive behavior of peers and (c) assess the program's face validity and social validity. The program was primarily based on cognitive-behavioral modification principles, procedures and techniques. Two hundred and thirty-seven students, drawn from six homeroom grade eight classes were randomly assigned to experimental and control (no intervention) conditions. The program consisted of seven units passed during twelve weekly one-hour sessions. Overall, the program had a positive effect on attitudes, emotions, knowledge and awareness of distress coping skills. In addition, it had some degree of face validity and social validity from the students' vantage point. These results lend support to the feasibility of a cognitive-behavioral, school-based prevention program for students' distress-coping enhancement.

Adaptation, Psychological↗
PubMed1996

Structure and dynamics of a protein assembly. 1H-NMR studies of the 36 kDa R6 insulin hexamer.

The structure and dynamics of the R6 human insulin hexamer are investigated by two- and three-dimensional homonuclear 1H-NMR spectroscopy. The R6 hexamer, stabilized by Zn2+ and phenol, provides a model of an allosteric protein assembly and is proposed to mimic aspects of receptor recognition. Despite the large size of the assembly (36 kDa), its extreme thermal stability permits high-resolution spectra to be observed at 55 degrees C. Each spin system is represented uniquely, implying either 6-fold symmetry or fast exchange among allowed protomeric conformations. Dramatic changes in chemical shifts and long-range nuclear Overhauser enhancements (NOEs) are observed relative to the spectra of insulin monomers. Complete sequential assignment is obtained and demonstrates native secondary structure with distinctive R-state N-terminal extension of the B-chain alpha-helix (residues B1 to B19). The distance-geometry structure of an R-state promoter is similar to those of R6 crystal structures. Specific long-range intra- and intersubunit NOEs, assigned by stepwise analysis of engineered insulin monomer and dimers, demonstrate that tertiary and quaternary contacts are also similar. Although the hexamer is well-ordered in solution, binding of phenol to an internal cavity occurs within milliseconds, implying the existence of "gatekeeper" residues whose flexibility provides a portal of entry and release. Changes in 1H-NMR chemical shifts on hexamer assembly are readily rationalized by analysis of aromatic ring-currents and provide sensitive probes for sites of protein-protein interaction and phenol binding. Our results provide a foundation for the interaction and phenol binding. Our results provide a foundation for the studies of insulin analogues (such as "designed" insulins of therapeutic interest) under conditions of clinical formulation and for the investigation of the effects of protein assembly on the dynamics of individual protomers.

Circular Dichroism↗
PubMed1999

Crystal structure of the stromelysin catalytic domain at 2.0 A resolution: inhibitor-induced conformational changes.

Matrix metalloproteinases are believed to play an important role in pathological conditions such as osteoarthritis, rheumatoid arthritis and tumor invasion. Stromelysin is a zinc-dependent proteinase and a member of the matrix metalloproteinase family. We have solved the crystal structure of an active uninhibited form of truncated stromelysin and a complex with a hydroxamate-based inhibitor. The catalytic domain of the enzyme of residues 83-255 is an active fragment. Two crystallographically independent molecules, A and B, associate as a dimer in the crystals. There are three alpha-helices and one twisted, five-strand beta-sheet in each molecule, as well as one catalytic Zn, one structural Zn and three structural Ca ions. The active site of stromelysin is located in a large, hydrophobic cleft. In particular, the S1' specificity site is a deep and highly hydrophobic cavity. The structure of a hydroxamate-phosphinamide-type inhibitor-bound stromelysin complex, formed by diffusion soaking, has been solved as part of our structure-based design strategy. The most important feature we observed is an inhibitor-induced conformational change in the S1' cavity which is triggered by Tyr223. In the uninhibited enzyme structure, Tyr223 completely covers the S1' cavity, while in the complex, the P1' group of the inhibitor displaces the Tyr223 in order to fit into the S1' cavity. Furthermore, the displacement of Tyr223 induces a major conformational change of the entire loop from residue 222 to residue 231. This finding provides direct evidence that Tyr223 plays the role of gatekeeper of the S1' cavity. Another important intermolecular interaction occurs at the active sit of molecule A, in which the C-terminal tail (residues 251-255) from molecule B inserts. The C-terminal tail interacts extensively with the active site of molecule A, and the last residue (Thr255) coordinated to the catalytic zinc as the fourth ligand, much like a product inhibitor would. The inhibitor-induced conformational change and the intermolecular C-terminal-zinc coordination are significant in understanding the structure-activity relationships of the enzyme.

Allosteric Regulation↗
PubMed1999

Estrogen promotes the initial migration and inception of NgCAM-dependent calcium-signaling by new neurons of the adult songbird brain.

The adult avian forebrain continues to generate neurons from ventricular zone (VZ) precursor cells, whose neuronal progeny then migrate into the brain parenchyma. Migrating neurons respond to the Ig-family adhesion molecule NgCAM with increments in cytosolic calcium, and migration is disrupted by anti-NgCAM Ig. The calcium response to NgCAM is developmentally restricted to bipolar migrants during a period spanning 6 to 9 DIV. This period corresponds to the postmitotic age at which new neurons leave the adult VZ to traverse a subjacent layer of estrogen-receptive "gatekeeper" neurons. Since neuronal passage through this layer occurs concurrently with the onset of NgCAM-dependent calcium signaling, we asked whether acquisition of the calcium response to NgCAM required estrogen exposure. Among neurons arising from explants of the adult finch neostriatal VZ, only those supplemented with estrogen developed calcium responses to NgCAM; neither explants raised in the absence of estrogen, nor those supplemented with testosterone, did so. Neurons in all three groups expressed NgCAM, had equivalent baseline calcium levels, and responded identically to K+-depolarization. Nonetheless, many more neurons migrated from explants of both finch and canary VZ raised in estrogen-supplemented media than from their estrogen-deprived counterparts, even though no effect of estrogen on neuronal survival per se was noted. These findings suggest that estrogen encourages the initial departure and assumption of signal competence by neurons arising from the adult avian VZ, thereby promoting their parenchymal recruitment and migration success.

Animals↗
PubMed1999

Peroxisomal very long chain fatty acid beta-oxidation activity is determined by the level of adrenodeukodystrophy protein (ALDP) expression.

Impaired peroxisomal beta-oxidation of saturated very long chain fatty acids (VLCFA, >/=C22:0) results in increased VLCFA levels in the tissues and body fluids of patients with disorders of peroxisomal biogenesis (i.e., Zellweger syndrome and neonatal adrenoleukodystrophy) and single peroxisomal protein defects (i.e., X-linked adrenoleukodystrophy (X-ALD) and acyl-CoA oxidase deficiency). We show that SV40T transformation also results in impaired peroxisomal beta-oxidation and VLCFA accumulation despite the presence of abundant peroxisomes. To explore the mechanism responsible for this observation, we have examined expression of key components of peroxisomal VLCFA beta-oxidation. We found that expression of both acyl-CoA oxidase, the rate limiting enzyme of peroxisomal VLCFA beta-oxidation and the adrenoleukodystrophy protein (ALDP), the defective gene product in X-ALD, are reduced after SV40T transformation. Surprisingly, ALDP overexpression by itself restores peroxisomal VLCFA beta-oxidation in SV40T-transformed control and X-ALD cells. These results demonstrate that ALDP is a fundamental component in VLCFA peroxisomal beta-oxidation and may serve as a "gatekeeper" for VLCFA homeostasis.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2000

Visualization of subthalamic nuclei with cortex attenuated inversion recovery MR imaging.

There is a significant amount of interest in studying the thalamus because of its central location in the brain and its role as a gatekeeper to higher centers of cognition. Imaging and measuring of the individual subnuclei of the thalamus has proven extremely difficult in MR because of the contrast-to-noise (CNR) of the MR sequences used. This report describes a novel MR pulse sequence known as cortex attenuated inversion recovery (CAIR), which increases the CNR in images and allows the individual subnuclei of the thalamus to be visualized by selectively nulling the gray matter in the brain using an inversion recovery sequence with an inversion time of 700 ms at 1.5 T.

Adult↗