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PubMed1995

Identifying adolescent drug users: results of a national survey on adolescent health in Switzerland.

OBJECTIVE: To explore the proportion and characteristics of adolescents who use illicit drugs and contrast them with adolescents who do not use such drugs in Switzerland. To facilitate the detection of adolescents with drug related difficulties. METHODS: We used data from a national survey on adolescent health in Switzerland (N = 9,273) conducted in 1992 and 1993. The survey is based on self-administered questionnaires among a representative sample of adolescents enrolled in schools and apprenticeship programs. We used exploratory analysis for identifying characteristics which set the drug user apart from non-users and performed confirmatory multivariate logistic regression analysis to examine which variables remain independently associated with heroin or cocaine use. RESULTS: In Switzerland, 3.1% of adolescents have taken heroin or cocaine at least once in their life, and 27.7% have already used cannabis. Analysis of lifestyles and health of adolescents show that young drug users present difficulties in integrating in society, have health problems and difficulties in relationships, situations which tend to be less common among other adolescents. Yet, they also display marked similarities, most notably in that over 70% had seen a physician in the past year. However, while 40% of the drug users expressed a need for help with drug related problems, only 6% had actually talked about them with a physician. Characteristics that remained independently associated with heroin and cocaine use after controlling for confounding factors were age, sex, nationality, type of education, feelings of suicide, past and present smoking, and use of cannabis. CONCLUSION: The level of illicit drug use among Swiss adolescents is high compared to other European countries but lower than the United States. Drug-using adolescents display a constellation of characteristics which should make it possible to identify them and offer help. Yet, even though they may have frequent contact with the health services, their drug problems are generally not recognized by the gatekeepers of the health services and no specific aid is available to them. Drug prevention must be intensified and medical doctors sensitized to the drug problems which adolescents may face.

Adolescent↗
PubMed2005

Comprehensive assessment of patients after coronary artery bypass grafting by 16-detector-row computed tomography.

BACKGROUND: Multidetector-row computed tomography (MDCT) is a versatile modality to evaluate stenoses in native coronary arteries and bypass grafts. Acquired MDCT data can additionally be used to assess left ventricular ejection fraction (LVEF). The purpose was to use MDCT for the assessment of bypass graft and coronary artery disease combined with evaluation of LVEF. METHODS: Twenty-five patients underwent 16-detector-row CT examination and coronary angiography. Bypass grafts and nongrafted coronary artery segments at MDCT were evaluated on eligibility, patency, and > or = 50% stenosis. The MDCT data set was used to calculate LVEF and was divided into patients with no/subendocardial/transmural myocardial infarctions (MIs). RESULTS: Ninety vessels were evaluated: 14 arterial grafts/53 vein grafts/23 nongrafted vessels. Of 225 segments, 17 were ineligible for evaluation because of metal clips. With MDCT, patency in segments of arterial grafts/vein grafts/nongrafted vessels could be evaluated with high accuracy in 100%/100%/97% of segments. In arterial grafts, stenoses > or = 50% did not occur at angiography, which was for all eligible segments correctly diagnosed at MDCT. Stenosis > or = 50% could be correctly detected by MDCT with a sensitivity/specificity of 100%/94% for vein grafts and 100%/89% for nongrafted vessels. Negative predictive value was 100% for vein grafts and nongrafted vessels. In patients with transmural MI, MDCT revealed a significant lower LVEF as compared with patients without or with subendocardial MI (P < .05). CONCLUSION: Comprehensive assessment of bypass grafts, nongrafted vessels, and LVEF is feasible with MDCT. Owing to the high negative predictive value this noninvasive approach may be used as gatekeeper before coronary angiography.

Aged↗
PubMed2004

Feasibility of assessment of coronary stent patency using 16-slice computed tomography.

Intracoronary stent implantation is a frequently performed procedure in the treatment of stenoses in coronary arteries, but in-stent restenosis occurs in approximately 10% to 15% of patients. A noninvasive diagnostic procedure to evaluate in-stent restenosis would therefore be of great benefit. We investigated the feasibility of assessing stent patency with 16-slice computed tomography. Multislice computed tomography (MSCT) was performed in 22 patients with previously implanted stents. For each stent, assessability was determined and related to stent type and diameter. Subsequently, the presence of significant restenosis was determined in the evaluable stents. In addition, peristent lumina (5 mm proximal and distal to the stent) were evaluated. Conventional angiography in combination with quantitative coronary angiography served as the standard of reference. MSCT was performed successfully in all but 1 patient. Of 65 stents, 50 (77%) were determined assessable. Uninterpretable stents tended to have a thicker strut and/or a smaller diameter. In the evaluable stents, 7 of 9 stenoses were detected and the absence of restenosis was correctly identified in all 41 patent stents, resulting in a sensitivity and specificity of 78% and 100%, respectively. Sensitivity and specificity for the detection of peristent stenosis were 75% and 96%, respectively. In conclusion, MSCT may be useful in the assessment of stent patency and may function as a gatekeeper before invasive diagnostic procedures.

Aged↗
PubMed2005

Strategies and issues for managing menopause-related symptoms in diverse populations: ethnic and racial diversity.

Menopause is a naturally occurring "equal opportunity" event that every woman who lives beyond the age of approximately 52 years will experience. During the next 20 years, approximately 3.5 million African American women, 2 million Latinas, and 1 million Asian American women will enter the menopause. How a woman approaches the menopausal transition depends on a number of factors, from educational level to socioeconomic status; health-related factors, including stress; and marital status. Increasingly, the roles of race and ethnicity, as they relate to menopausal symptoms, are being explored. Understanding similarities and differences among women of color in perceptions, attitudes, and expectations surrounding the menopause can help provide culturally appropriate care and promote lifestyles that may decrease symptoms and increase quality of life. For example, minority women are usually the gatekeepers for healthcare for themselves and their families and have a highly developed social support network, often including extended family, a church community, and involvement in sororal or social organizations. In the future, research on menopausal symptoms among women of different racial/ethnic groups should focus on exploring in greater detail the effect of dietary factors and body mass index, additional evaluation of pituitary sensitivity, and use of complementary and alternative medicines in symptom management, with a better understanding of the risks and benefits of such therapies.

Complementary Therapies↗
PubMed2005

Conformational detours during folding of a collapsed state.

The protein S6 is a useful model to probe the role of partially folded states in the folding process. In the absence of salt, S6 folds from the denatured state D to the native state N without detectable intermediates. High concentrations of sodium sulfate induce the accumulation of a collapsed state C, which is off the direct folding route. However, the mutation VA85 enables S6 to fold from C directly to N through the transition state TS(C). According to the denaturant dependence of this reaction, TS(C) and C are equally compact, but the data are difficult to deconvolute. Therefore, I have measured the heat capacities (DeltaC(p)) for the D-->C and C-->TS(C) transitions. The DeltaC(p)-values suggest that C needs to increase its surface area in order to fold directly to N. This underlines that it is a misfolded state that can only fold by at least partial unfolding. In contrast to the C-state formed by S6 wildtype, the VA85 C-state is just as compact as the native state, and this may be a prerequisite for direct folding. Individual "gatekeeper" residues may thus play a disproportionately large role in guiding proteins through different folding pathways.

Bacterial Proteins↗
PubMed2004

Transferrin receptor 1.

With the discovery that transferrin serves as the iron source for hemoglobin-synthesizing immature red blood cells came the demonstration that a cell surface receptor, now known as transferrin receptor 1, is required for iron delivery from transferrin to cells. (A recently described second transferrin receptor, with as yet poorly understood function, will not be discussed in this brief review.) In succeeding years transferrin receptor 1 was established as a gatekeeper for regulating iron uptake by most cells, and the transferrin-to-cell endocytic pathway characterized in detail. HFE, the protein incriminated in the pathogenesis of hereditary hemochromatosis, a disorder of progressive and toxic iron overload, competes with transferrin for binding to receptor, thereby impeding the uptake of iron from transferrin. Mutation of HFE destroys this competition, thus facilitating access of transferrin and its iron to cells. Availability of the crystal structure of transferrin receptor 1, along with those of transferrin and HFE, opened research on molecular mapping of the transferrin-HFE- transferrin receptor interfaces by correlated synchrotron-generated hydroxyl radical footprinting and cryo-electron microscopy. The emerging challenge is to relate structure to the functional effects of receptor binding on the iron-binding and iron-releasing properties of transferrin within the iron-dependent cell.

Antigens, CD↗
PubMed2005

Glucose transport to the brain: a systems model.

Glucose transport to the brain involves sophisticated interactions of solutes, transporters, enzymes, and cell signaling processes, within an intricate spatial architecture. The dynamics of the transport are influenced by the adaptive nature of the blood-brain barrier (BBB), the semi-impermeable membranes of brain capillaries. As both the gate and the gatekeeper between blood-borne nutrients and brain tissue, the BBB helps govern brain homeostasis. Glucose in the blood must cross the BBB's luminal and abluminal membranes to reach neural tissue. A robust representation of the glucose transport mechanism can highlight a target for brain therapeutic intervention, help characterize mechanisms behind several disease phenotypes, or suggest a new delivery route for drugs. The challenge for researchers is understanding the relationships between influential physiological variables in vivo, and using that knowledge to predict how alterations or interventions affect glucose transport. This paper reviews factors influencing glucose transport and approaches to representing blood-to-brain glucose transport including in vitro, in vivo, and kinetic models. Applications for different models are highlighted, while their limitations in answering arising questions about the human in vivo BBB lead to a discussion of an alternate approach. A developing complex systems simulation is introduced, initiating a single platform to represent the dynamics of glucose transport across the adapting human blood-brain barrier.

Animals↗
PubMed2026

Mirror worlds: The shared regulatory architecture of cell fate in development and cancer.

Lineage plasticity has emerged as a central mechanism through which cancer cells adapt to therapeutic pressure, evade immune surveillance, and acquire aggressive phenotypes. Although recognized across tumor types, the regulatory principles governing how cancer cells reprogram cellular identity remain incompletely understood. In this review, we propose that lineage plasticity in cancer reflects the redeployment of regulatory frameworks established during normal development. Rather than representing a stochastic byproduct of genomic instability, cancer plasticity frequently unfolds within gene regulatory architectures that also govern cell fate specification, lineage commitment, and controlled state transitions during embryogenesis and tissue homeostasis. Developmental transcription factors, including members of the SOX family, FOXA1, ASCL1, NKX2-1, and epithelial-mesenchymal transition regulators, function as lineage gatekeepers during development but are repurposed in cancer to destabilize lineage commitment and enable phenotypic switching. Similarly, epigenetic regulators that guide developmental trajectories, including chromatin remodeling complexes, Polycomb group proteins, and DNA methylation machinery, are frequently dysregulated or redistributed in tumors, altering the repression of lineage-stabilizing and alternative lineage programs and thereby weakening epigenetic barriers to lineage transitions. Together, these observations support a model in which development and cancer operate as mirror regulatory systems: one establishing and stabilizing cellular identity, the other exploiting the same regulatory architecture to permit adaptive reprogramming under selective pressure. We further discuss how emerging single-cell and spatial multi-omics technologies, integrated with artificial intelligence-based modeling, enable mapping of cell state landscapes and transitional trajectories, transforming lineage plasticity from a descriptive phenomenon into a measurable and predictable property of tumor evolution.

Humans↗
PubMed2006

A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation.

How the ER-associated degradation (ERAD) machinery accurately identifies terminally misfolded proteins is poorly understood. For luminal ERAD substrates, this recognition depends on their folding and glycosylation status as well as on the conserved ER lectin Yos9p. Here we show that Yos9p is part of a stable complex that organizes key components of ERAD machinery on both sides of the ER membrane, including the transmembrane ubiquitin ligase Hrd1p. We further demonstrate that Yos9p, together with Kar2p and Hrd3p, forms a luminal surveillance complex that both recruits nonnative proteins to the core ERAD machinery and assists a distinct sugar-dependent step necessary to commit substrates for degradation. When Hrd1p is uncoupled from the Yos9p surveillance complex, degradation can occur independently of the requirement for glycosylation. Thus, Yos9p/Kar2p/Hrd3p acts as a gatekeeper, ensuring correct identification of terminally misfolded proteins by recruiting misfolded forms to the ERAD machinery, contributing to the interrogation of substrate sugar status, and preventing glycosylation-independent degradation.

Amino Acid Sequence↗
PubMed2006

OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.

Mitochondria amplify activation of caspases during apoptosis by releasing cytochrome c and other cofactors. This is accompanied by fragmentation of the organelle and remodeling of the cristae. Here we provide evidence that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion. OPA1 does not interfere with activation of the mitochondrial "gatekeepers" BAX and BAK, but it controls the shape of mitochondrial cristae, keeping their junctions tight during apoptosis. Tightness of cristae junctions correlates with oligomerization of two forms of OPA1, a soluble, intermembrane space and an integral inner membrane one. The proapoptotic BCL-2 family member BID, which widens cristae junctions, also disrupts OPA1 oligomers. Thus, OPA1 has genetically and molecularly distinct functions in mitochondrial fusion and in cristae remodeling during apoptosis.

Animals↗
PubMed2005

Structure-based engineering of E. coli galactokinase as a first step toward in vivo glycorandomization.

In vitro glycorandomization is a rapid chemoenzymatic strategy to diversify complex natural product scaffolds. The glycorandomization sugar activation pathway is dependent upon the efficient construction of diverse sugar-1-phosphate libraries. In the context of the previously evolved GalK Y371H "gatekeeper" mutation, the active site M173L mutation described herein presents a kinase with remarkably broadened substrate range to include 28 diverse natural and unnatural sugars. Among these new substrates, 6-azido-6-deoxy-galactose and 6-azido-6-deoxy-glucose present unique chemical probes to assess the utility of an E. coli Y371H/M173L-GalK-overproducing strain to generate unnatural sugar-1-phosphates in vivo. Remarkably, the in vivo conversion of both unnatural sugars rival that demonstrated in vitro. This notable in vivo success stands as the first step toward constructing short sugar-activation pathways in vivo and, ultimately, in vivo natural-product glycorandomization.

Binding Sites↗
PubMed2005

Toll-like receptors in giant cell arteritis.

Giant cell arteritis, a primary vasculitis of medium-sized and large arteries, causes vessel occlusion through fast and concentric intimal hyperplasia. Contextual parameters, especially the topography of the arterial wall, have emerged as critical pathogenic elements. Experimental data support the concept that the disease is initiated in the most outer layer of the arterial wall, the adventitia. CD4 T cells are recruited to the adventitia, undergo local activation and subsequently orchestrate macrophage differentiation. T cells and macrophages infiltrate into all wall layers and acquire different effector functions dependent on cues in their immediate microenvironment. The end result is myofibroblastic proliferation, luminal stenosis, and tissue ischemia. Adaptive immune responses in the adventitia are triggered by a population of indigenous dendritic cells (DC) placed at the adventitia-media junction. These arterial DCs have a unique surface receptor profile, including a series of Toll-like receptors (TLR). Responsiveness of such arterial DCs to blood-borne stimuli has been studied in human arteries engrafted into immunodeficient mice. Ligands of TLR4 are able to start maturation of adventitial DCs which fail to leave the peripheral tissue site. Instead, these adventitial DCs produce chemokines, recruit T cells, and support their local activation. These data identify tissue-residing DCs as gatekeepers in vasculitis and support the model that TLR ligands function as instigators of vessel wall inflammation.

Animals↗
PubMed2004

Critical care nursing for older adults: pathophysiological and functional considerations.

The aging of the population brings into health care practice, including ICUs, an increasing prevalence of people with chronic conditions with corresponding expectations of eventual decline in function. These age-related health problems, however, do not have a precise moment of onset, nor a single and unambiguous cause. By their nature, chronic conditions do not have an end that can be modified easily, and ordinarily, they are related to parameters other than physiology alone. Aged individuals often are distinguished as a medicalized cohort on the basis of sheer numbers of comorbidities and predisposition toward frequent hospitalizations, without regard for the potential for adaptation to life despite complex health factors. Some care providers, health economists, and bioethicists propose using the existence of chronic conditions and assumed physical decompensation asa valid basis for restricting individuals and groups, by means of rationing, from consideration for intensive care and treatment. In view of studies demonstrating that covert rationing of ICU resources to critically ill older patients already is taking place, there isa need to continue to examine institutional policies that permit care providers to act as gatekeepers, ostensibly with benign intent, but presumably without patients' knowledge or acceptance. On the other hand, there is evidence that older ICU patients do equally well as younger and middle-aged patients in terms of discharge from the hospital with subsequent recovery of function. Thus, age alone is not a useful marker for limiting access to ICUs. Rather, a comprehensive evaluation is the foundation for diagnostic accuracy and health care decision-making for older individuals. Assessment and maintenance of the older person's functional status are fundamental concerns of geriatric and critical care specialists. Evaluation of an individual's baseline abilities in physical, mental, social, and psychological spheres is necessary before limitation of care realistically can be considered. Intensive care unit hospitalizations for catastrophic or critical illness are not necessarily terminal events. Ongoing functional assessment will help to illuminate the impact of chronicity on an older person's capacity for self care, and may help to guide health care decision-making regarding use of critical care resources. Accordingly, assuring equitable access to essential intensive care services, devoid of concerns about age constraints, will help to ensure the autonomy that is central to older adults' achievement of a fulfilling and productive old age.

Aged↗
PubMed2006

16-detector row computed tomographic coronary angiography in patients undergoing evaluation for aortic valve replacement: comparison with catheter angiography.

AIM: To evaluate the diagnostic accuracy of 16-detector row computed tomography (CT) in assessing haemodynamically significant coronary artery stenoses in patients under evaluation for aortic stenosis pre-aortic valve replacement. SUBJECTS AND METHODS: Forty consecutive patients under evaluation for severe aortic stenosis and listed for cardiac catheterization before potential aortic valve replacement underwent coronary artery calcium (CAC) scoring and retrospective electrocardiogram (ECG)-gated multi-detector row computed tomographic coronary angiography (MDCTA) using a GE Lightspeed 16-detector row CT within 1 month of invasive coronary angiography (ICA) for comparative purposes. All 13 major coronary artery segments of the American Heart Association model were evaluated for the presence of > or =50% stenosis and compared to the reference standard. Data were analysed on a segment-by-segment basis and also in "whole patient" terms. RESULTS: A total of 412/450 segments from 35 patients were suitable for analysis. The overall accuracy of MDCTA for detection of segments with > or =50% stenosis was high, with a sensitivity of 81.3%, specificity 95.0%, positive predictive value (PPV) 57.8%, and negative predictive value (NPV) 98.4%. On a "whole-patient" basis, 100% (19/19) of patients with significant coronary disease were correctly identified and there were no false-negatives. Excluding patients with CAC >1000 from the analysis improved the accuracy of MDCTA to: sensitivity 90%, specificity 98.1%, PPV 60%, NPV 99.7%. CONCLUSION: Non-invasive 16-detector row MDCTA accurately excludes significant coronary disease in patients with severe aortic stenosis undergoing evaluation before aortic valve replacement and in whom ICA can therefore be avoided. Its segment-by-segment accuracy is improved further if CAC>1000 is used as a gatekeeper to MDCTA.

Adult↗
PubMed2006

Axon guidance: ephrins at WRK on the midline.

Recent findings indicate that the embryonic motor neurons act as gatekeepers to regulate midline crossing during development of the nematode Caenorhabditis elegans. The newly identified protein WRK-1 and ephrins cooperate to prevent longitudinal axons from crossing the midline.

Animals↗
PubMed2005

Adhesion molecules in inflammatory bowel disease: therapeutic implications for gut inflammation.

Mucosal endothelium has become one of the major areas of investigation in gut inflammation. It is now well recognised that it plays an active role in the pathogenesis of both forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis, since endothelial cells regulate mucosal immune homeostasis, acting as "gatekeepers", controlling leukocyte accumulation in the interstitial compartment. This process is mediated by leukocyte-endothelial adhesion molecules. This paper reviews the major molecules that mediate leukocyte-endothelial interactions, and summarises the results of the most recent clinical trials targeting adhesion molecules in inflammatory bowel disease.

Animals↗
PubMed2006

The changing immunological paradigm in coeliac disease.

When coeliac disease is referred to as an inflammatory disorder, this may detract from its true nature. Activation of innate and adaptive immunity takes place in the mucosal lesion, but the tissue reaction is not that of classical inflammation. In fact, coeliac disease contrasts strikingly with typical inflammatory bowel disorders such as ulcerative colitis and Crohn's disease. The coeliac lesion apparently reflects, in the main, immune-driven remodelling of mucosal architecture with only a minor inflammatory component - initially most likely resulting from innate signals. Complement split products might be one of several potential initial hits that lead to activation of lamina propria and epithelial cells with release of mediators such as interleukin-15. This cytokine appears to stimulate potentially pathogenic intraepithelial lymphocytes. In genetically susceptible individuals, such early innate events could turn into persistent pathogenic signalling with subsequent adaptive cellular and humoral immunopathology resulting in a chronic lesion. Nevertheless, mucosal homeostasis is surprisingly well preserved as signified by the remarkable dominance of plasma cells that produce dimeric immunoglobulin A as a basis for enhanced secretory immunity. This shows that the microvascular endothelium in the lesion largely maintains its 'gatekeeper' function for mucosal immune cells - in striking contrast to the 'promiscuous' situation in inflammatory bowel disease. Altogether, a two-signal model is emerging for the pathogenesis of coeliac disease - signal 1 generated by innate immunity and signal 2 by adaptive immunity. Hence, there is currently an increased focus on immune activation in the epithelial compartment rather than on changes in the microvasculature as a basis for classical inflammation.

Animals↗
PubMed2005

Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression.

The lethal outcome of high-dose pulmonary virus infection is thought to reflect high-level, sustained virus replication and associated lung inflammation prior to development of an adaptive immune response. Herein, we demonstrate that the outcome of lethal/sublethal influenza infection instead correlates with the initial virus replication tempo. Furthermore, the magnitude of early lung antiviral CD8+ T cell responses varies inversely with inoculum dose and is controlled by lymph-node-resident dendritic cells (LNDC) through IL-12p40-regulated FasL-dependent T cell apoptosis. These results suggest that the inoculum dose and replication rate of a pathogen entering the respiratory tract may regulate the strength of the adaptive immune response, and the subsequent outcome of infection and that LNDC may serve as regulators (gatekeepers) in the development of CD8+ T cell responses.

Adoptive Transfer↗