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PubMed2026

USP10-SIRT6-PARP1 axis drives keratinocyte senescence and skin photoaging under chronic UVA exposure.

Chronic exposure to ultraviolet A (UVA) radiation is the principal environmental driver of skin photoaging, yet the upstream molecular events that commit irradiated keratinocytes to senescence remain poorly understood. Here we show that SIRT6, an NAD+-dependent protein deacetylase with established roles in genome maintenance and organismal longevity, functions as a central gatekeeper of keratinocyte homeostasis under photic stress. Using a chronic UVA irradiation model in mice together with cultured human keratinocytes, we demonstrate that UVA inflicts extensive DNA damage and G2/M cell-cycle arrest, accompanied by selective depletion of SIRT6 among all sirtuin family members. Mechanistically, UVA suppresses the deubiquitinase USP10 at both transcriptional and post-transcriptional levels, thereby licensing ubiquitin-dependent proteasomal degradation of SIRT6. The resulting SIRT6 deficiency unleashes hyperactivation of the DNA-damage sensor PARP1, amplifying genomic injury signaling and driving keratinocytes into irreversible senescence with concomitant elaboration of a broad pro-inflammatory secretory programme encompassing chemokines and cytokines. Pharmacological reactivation of SIRT6 with the selective agonist UBCS039 reverses epidermal hyperplasia, attenuates DNA damage and senescence marker accumulation, and suppresses inflammatory mediator induction both in vivo and in vitro, establishing SIRT6 loss as a causal rather than correlative event. Furthermore, molecular docking and functional validation identify osthole, a plant-derived coumarin from the medicinal herb Cnidium monnieri, as a candidate SIRT6-engaging compound that counteracts UVA-induced senescence and inflammation in keratinocytes. Collectively, these findings define a USP10-SIRT6-PARP1 signaling axis whose disruption underlies cutaneous photoaging and suggest that SIRT6-directed strategies may offer therapeutic benefit against UV-driven tissue degeneration.

Animals↗
PubMed2006

Pre-operative computed tomography coronary angiography to detect significant coronary artery disease in patients referred for cardiac valve surgery.

OBJECTIVES: We studied the diagnostic performance of 64-slice computed tomography coronary angiography (CTCA) to rule out or detect significant coronary stenosis in patients referred for valve surgery. BACKGROUND: Invasive conventional coronary angiography (CCA) is recommended in most patients scheduled for valve surgery. METHODS: During a 6-month period, 145 patients were prospectively identified from a consecutive patient population scheduled for valve surgery. Thirty-five patients were excluded because of CTCA criteria: irregular heart rhythm (n = 26), impaired renal function (n = 5), and known contrast allergy (n = 4). General exclusion criteria were: hospitalization in community hospital (n = 4), no need for CCA (n = 4), previous coronary artery bypass surgery (n = 1), or percutaneous coronary intervention (n = 4). Of the remaining 97 patients, 27 denied written informed consent. Thus, the study population comprised 70 patients (49 male, 21 female; mean age 63 +/- 11 years). RESULTS: Prevalence of significant coronary artery disease, defined as having at least 1 > or =50% stenosis per patient, was 25.7%. Beta-blockers were administered in 71%, and 64% received lorazepam. The mean heart rate dropped from 72.5 +/- 12.4 to 59.5 +/- 7.5 beats/min. The mean scan time was 12.8 +/- 1.3 s. On a per-patient analysis, the sensitivity, specificity, and positive and negative predictive values were: 100% (18 of 18; 95% confidence interval [CI] 78 to 100), 92% (48 of 52; 95% CI 81 to 98), 82% (18 of 22; 95% CI 59 to 94), and 100% (48 of 48; 95% CI 91 to 100), respectively. CONCLUSIONS: The diagnostic accuracy of 64-slice CTCA for ruling out the presence of significant coronary stenoses in patients undergoing valve surgery is excellent and allows CTCA implementation as a gatekeeper for invasive CCA in these patients.

Adrenergic beta-Antagonists↗
PubMed2006

Rethinking the associations between television viewing and adolescent sexuality development: bringing gender into focus.

PURPOSE: To investigate associations between adolescents' television viewing, their sexual behavior, and their perceptions of having power and control in sexual situations (i.e., sexual agency). This study incorporates results from a recent content analysis of television and attends to the different motives for and consequences of girls' and boys' sexual and relational behavior. METHODS: Adolescents (n = 703) aged 11 to 17 years from two public school districts in the Northeastern United States completed surveys assessing their television habits and sexual experiences. Survey data were combined with two content analyses, which assessed the frequency of sexual talk and behavior and the prevalence of gendered messages about sexuality (i.e., the Heterosexual Script) on primetime network television. RESULTS: Adolescents' sexual behavior and feelings of sexual agency were not associated with viewing sexual talk and sexual behavior on television, but were related to viewing the Heterosexual Script, particularly among girls. Girls who saw sexually objectified women and portrayals of men avoiding commitment more often reported less sexual agency. Girls who saw women acting as sexual gatekeepers more often were less sexually experienced and reported more sexual agency. Boys who saw men actively asserting their sexuality more often were less sexually experienced. CONCLUSIONS: The relationship between adolescents' television viewing and sexual experiences depends on the type of sexual messages viewed, the sexual outcome considered, and the gender of the viewer. Parents and practitioners should learn to identify the Heterosexual Script on television and encourage young people to negotiate sexual encounters in safe and positive ways.

Adolescent↗
PubMed2004

Crystal structure of putidaredoxin reductase from Pseudomonas putida, the final structural component of the cytochrome P450cam monooxygenase.

The crystal structure of recombinant putidaredoxin reductase (Pdr), an FAD-containing NADH-dependent flavoprotein component of the cytochrome P450cam monooxygenase from Pseudomonas putida, has been determined to 1.90 A resolution. The protein has a fold similar to that of disulfide reductases and consists of the FAD-binding, NAD-binding, and C-terminal domains. Compared to homologous flavoenzymes, the reductase component of biphenyl dioxygenase (BphA4) and apoptosis-inducing factor, Pdr lacks one of the arginine residues that compensates partially for the negative charge on the pyrophosphate of FAD. This uncompensated negative charge is likely to decrease the electron-accepting ability of the flavin. The aromatic side-chain of the "gatekeeper" Tyr159 is in the "out" conformation and leaves the nicotinamide-binding site of Pdr completely open. The presence of electron density in the NAD-binding channel indicates that NAD originating from Escherichia coli is partially bound to Pdr. A structural comparison of Pdr with homologous flavoproteins indicates that an open and accessible nicotinamide-binding site, the presence of an acidic residue in the middle part of the NAD-binding channel that binds the nicotinamide ribose, and multiple positively charged arginine residues surrounding the entrance of the NAD-binding channel are the special structural elements that assist tighter and more specific binding of the oxidized pyridine nucleotide by the BphA4-like flavoproteins. The crystallographic model of Pdr explains differences in the electron transfer mechanism in the Pdr-putidaredoxin redox couple and their mammalian counterparts, adrenodoxin reductase and adrenodoxin.

Amino Acid Sequence↗
PubMed2004

Hemodynamic and clinical impact of ultrasound-derived venous reflux parameters.

PURPOSE: This study was undertaken to assess which ultrasound-derived parameter was superior for measuring venous reflux quantitatively and to evaluate the importance of popliteal vein valve reflux. PATIENTS AND METHODS: A retrospective analysis was performed of 244 refluxive limbs in 182 patients who underwent ultrasound scanning, venous pressure measurement, air plethysmography, and clinical classification of severity according to the CEAP score. Reflux time (RT, s), peak reflux velocity (PRV, m/s), time of average rate of reflux (TAF, mL/min), absolute displaced volume retrogradely (ADV, mL) were compared to clinical class, ambulatory venous pressure (% drop), venous filling time (s), and venous filling index (mL/s) using nonparametric statistical tests. A P value of <.05 was considered significant. Limbs were divided into 3 groups: (A) axial great saphenous vein reflux only (n = 68); (B) axial deep reflux including popliteal vein incompetence with or without concomitant gastrocnemius or great or small saphenous vein reflux (all ultrasound reflux parameters of each refluxive vein added at the knee level) (n = 79); and (C) all limbs with popliteal vein reflux (the ultrasound data of the refluxive popliteal vein exclusively was used in comparison regardless of concomitant associated reflux) (n = 103). Limbs were also stratified into limbs with skin changes and ulcer (C-class 4-6) and those without (C-class 1-3) and subsequently compared. RESULTS: No meaningful significant correlation was found between RT and the clinical and hemodynamic results in groups A and B. The PRV and TAF correlated significantly with the hemodynamic parameters. The PRV and TAF and clinical severity trended towards correlation in group A (P =.0554 and P =.0998, respectively), but was significantly correlated in group B. The poor hemodynamic condition in the subset of C-class 4-6 limbs in groups A and B was reflected in a greater PRV, TAF, and ADV in this subset as compared with the limbs in C-class 1-3. RT was not significantly different in the subsets of limbs, further suggesting that RT is not related to hemodynamic or clinical state of the limbs. No meaningful correlations were found in group C. Although the hemodynamic data were significantly poorer in the subset of limbs with C-class 4-6 than in C-class 1-3, the ultrasound-derived parameters were not significantly different. CONCLUSION: The duration of valve reflux time (or valve closure time) cannot be used to quantify severity of reflux and is purely a qualitative measurement. The PRV and the rate of reflux appeared to better reflect the magnitude of venous incompetence. In the presence of axial reflux, it appeared logical and physiologically correct to sum up these reflux parameters for each venous segment crossing the knee. The popliteal valve reflux (the "gatekeeper" function) was not in itself an important determinant of venous hemodynamics and clinical severity. Additional reflux in other venous segments must be taken into account.

Adolescent↗
PubMed2005

Caveolin-1 as a prime modulator of aging: a new modality for phenotypic restoration?

Aging can be characterized by structural changes and functional deterioration during the lifetime, for which hundreds of explanations have been put forward. Recently, we have proposed the gate theory of aging, in which gatekeeper molecules at the membrane level would play the prime role in determining the senescent phenotype. Caveolin-1 would be a prime candidate for such a role as a major determinant of the aging process. Caveolin-1 can associate with a variety of molecules, involved in signal transduction, endocytosis and transcytosis, cytoskeletal arrangement, etc. The level of caveolin-1 is strictly regulated to maintain cellular integrity, leading to cellular transformation if depleted, and to the senescent phenotype if overexpressed. In case of senescent cells, the functional and physiological responses to the mitogenic stimuli can be restored and the morphological shape can be resumed by simple adjustment of caveolin-1 status. Therefore, it is suggested that prime modulator molecules, represented by caveolin-1, play a key role in determining the senescent phenotype, either as a physiological response or altered morphology.

Animals↗
PubMed2006

Novel signals for the integration of energy balance and reproduction.

Although the close link between body weight and fertility has been known for eons, only recently have the peripheral signals and neuroendocrine networks responsible for such a phenomenon begun to be identified. A key event in this field was the cloning of the adipocyte-derived hormone leptin, which has been demonstrated as a pivotal regulator for the integration of energy homeostasis and reproduction. In addition, other metabolic hormones, such as insulin, contribute to this physiological integration. Moreover, compelling experimental evidence implicates hormonal products of the gastrointestinal tract as adjuncts in the complex coordination and regulation of body weight and reproduction. Here, we review recent studies evaluating the reproductive effects and sites of action of ghrelin and PYY3-36, two hormonal signals of gastrointestinal origin involved in the control food intake and energy balance. In addition, we summarize the potential contribution of kisspeptin, the recently characterized gatekeeper of the GnRH system encoded by Kiss1 gene, to integrating reproductive function and energy status. Evidence suggests that besides having direct gonadal effects, ghrelin may participate in the regulation of gonadotropin secretion and it may influence the timing of puberty. Likewise, PYY3-36 modulates GnRH and gonadotropin release. In addition, the hypothalamic KiSS-1 system is sensitive to nutritional status, and its diminished expression during states of negative energy balance might contribute to the suppression of reproductive function in such conditions. We propose that the peripheral hormones, ghrelin and PYY3-36, and the central neuropeptide, kisspeptin, are 'novel' players in the neuroendocrine networks that integrate energy balance and reproduction.

Animals↗
PubMed2006

Nurses' experiences of continuing professional development.

Continuing professional development is regarded as part of the nursing role in the National Health Service. Health policy in the United Kingdom is built on the assumption that nurses' roles can be extended through continuing professional development which is also considered to be a key factor in nursing retention. Previous research has considered the provision of learning mainly from the perspective of managers and education providers. The purpose of this paper is to explore nurses' experiences of continuing professional development. The results presented in this paper form part of a larger survey (n=451, response rate=64.9%) designed to examine opportunities for continuing professional development and factors encouraging and discouraging uptake. An unexpectedly high number of respondents (n=125, 27.7%) commented extensively on their personal experiences of continuing professional development. These comments were analysed inductively. Five main themes emerged: who and what is continuing professional development for?; accessing continuing professional development; one size does not fit all; managing work, life and doing continuing professional development; and making the best of continuing professional development. Most responses were positive, but the demands of taking courses were perceived to encroach on life outside work, especially the need to complete lengthy assignments. Managers were perceived to operate as the gatekeepers to course admission and opportunities to implement new knowledge and expertise. No comments were received concerning the role of education staff in continuing professional development.

Adaptation, Psychological↗
PubMed2004

Special report: reassessment of the ORL-HNS workforce: perceptions and realities.

OBJECTIVE: This Workforce Study re-examined the current scope and geographic distribution of Otolaryngology practice and assessed the otolaryngologists' role in relation to other specialists in the diagnosis and treatment of disorders of the ear, nose, throat, and related structures of the head and neck. Study design A national survey and review of federal, corporate and administrative databases, coupled wih a focus group of otolaryngologists, were analyzed to compile physician manpower figures, state and regional demographic data, and prediction modeling of Managed Care and FFS environments. RESULTS: The current and predicted workforce supply and demographic data support a geographic and proportionate increase in the number of otolaryngologists practicing and entering the workforce. Additional findings involving the role of the specialty specifically identified an increase in the treatment of allergic disease within the Managed Care sector and a diminution of the gatekeeper concept. Demographic findings represent a stable age distribution of 40 to 49 and 50 to 59 year old otolaryngologists, with a noted increase in the number of women entering the field. Empiric data reflects the continuous, diverse and dominant role otolaryngologists maintain in the treatment and care of patients with otolaryngologic and head and neck disease. CONCLUSIONS: This study continues the effort to identify otolaryngology workforce demographic profiles and make recommendations for a future national practice model. Continuous reassessment of the specialty is required.

Adult↗
PubMed2006

Dermatologic emergencies.

Primary care physicians are the gatekeepers of the medical community. They are the physicians to whom patients first present, and they are often the physicians with whom patients have the longest lasting relationships. Primary care physicians, as a result of these long-term relationships, have been endowed with a unique responsibility to the health of their patients. By the very nature of their practice, primary care physicians do not have the resources to treat emergent life-threatening conditions. They must, however, be able to diagnose these potentially life-threatening conditions and be able to stabilize and appropriately refer a patient for urgent evaluation by specialists or emergency physicians. There are many types of emergencies encountered in the outpatient setting, ranging from cardiac to toxicologic. As important as recognizing signs and symptoms of cardiac ischemia is the ability to recognize potentially life-threatening dermatologic disorders or dermatologic manifestations of life-threatening systemic diseases.

Emergencies↗
PubMed2006

Using aggregate data on dispensed drugs to evaluate the quality of prescribing in urban primary health care in Sweden.

BACKGROUND: Valuable evaluations of the quality of drug prescribing in routine health care are difficult to perform. It is even more difficult to study prescribing in a non-gatekeeping healthcare system with a variety of caregivers involved in patient care. Consequently, there is a need to develop methods for evaluation using data available in routine health care. OBJECTIVES: The aim of this study was to analyse possibilities and limitations for evaluation of the quality of drug prescribing using routinely collected aggregate data on dispensed drugs and health care provision. A secondary aim was to study the effects of allocating more resources to primary health care (PHC) on the quality of drug prescribing. METHODS: The study was performed with routinely collected data from 10 PHC centres in Stockholm, Sweden that were participating in an intervention project that aimed to decrease the number of inhabitants per PHC doctor. Time periods for analysis were October-December 1999, 2000 and 2001. Data on dispensed prescriptions were analysed by age using Anatomical Therapeutic Chemical (ATC) classification/defined daily dose (DDD) methodology. The general quality of prescribing was determined using DU90% methodology (identifying the number of drugs constituting 90% of the volume expressed in DDDs and the adherence to evidence-based recommendations) and ratios between different treatment alternatives. The total volume and cost of drugs prescribed to the population was also analysed. RESULTS: In 2001, PHC centres accounted for, on average, 27% (range 14-36%) of all doctor consultations and 32% (range 22-43%) of all prescriptions to populations in the corresponding primary care districts. There was great variation between the different PHC centres with regard to the prescribing doctors' compliance with guidelines from the regional drug and therapeutics committee, and the utilization of health care and drugs among the population in the corresponding primary care districts. No clear improvement was observed over time. CONCLUSION: Analysis of aggregated prescription and healthcare data at population level was feasible. However, the effects of allocation of increasing resources to PHC on the quality of drug prescribing need to be analysed in a broader context.

Adolescent↗
PubMed2004

The epigenetics of cancer etiology.

Epigenetic dysregulation is central to cancer development and progression. This dysregulation includes hypomethylation leading to oncogene activation and chromosomal instability, hypermethylation and tumor suppressor gene silencing, and chromatin modification acting directly, and cooperatively with methylation changes, to modify gene expression. In addition, disrupted genomic imprinting appears to contribute to colorectal cancer risk, and serves as a gatekeeper in Wilms tumor. A cancer predisposing disorder, Beckwith-Wiedemann syndrome, usually arises from epigenetic errors, solidifying the causal role of epigenetics in cancer. While cancer epigenetics has been reviewed extensively elsewhere, the main focus of this review will be to present the view that epigenetics and genetics are complementary in the area of cancer etiology, the focus of this volume. I propose a hypothesis in which epigenetic alterations contribute to tumor progression, but they also increase the probability that genetic changes, when they occur, will lead to cancer initiation. This hypothesis could contribute to a new understanding of the role of environmental carcinogens that may not be fully explained through a purely genetic view or by tests, such as bacterial mutation frequency, that ignore epigenetic factors.

Animals↗
PubMed2005

Molecular mechanisms of cholesterol absorption and transport in the intestine.

Many enzymes and transport proteins participate in cholesterol absorption. This review summarizes recent results on several proteins that are important for each step of the cholesterol absorption pathway, including the important roles of: (i) pancreatic triglyceride lipase (PTL), carboxyl ester lipase (CEL), and ileal bile acid transporter in determining the rate of cholesterol absorption; (ii) ATP binding cassette (ABC) transporters and the Niemann-Pick C-1 like-1 (NPC1L1) protein as intestinal membrane gatekeepers for cholesterol efflux and influx; and (iii) intracellular membrane vesicles and transport proteins in lipid trafficking through intracellular compartments prior to lipoprotein assembly and secretion to plasma circulation.

ATP-Binding Cassette Transporters↗
PubMed2003

Chemokine regulation of naïve T cell traffic in health and disease.

A central feature of the immune response is the precise spatio-temporal convergence of T cells and antigen presenting cells (APC) in particular microenvironments within secondary lymphoid organs (SLO). CCR7 and its ligands CCL19 and CCL21 have been identified as the gatekeepers for both naïve T lymphocytes and dendritic cells (DC) to these defined anatomical compartments. A new perception on the regulation of lymphocyte traffic in lymph nodes (LN) has come from observations that sphingosine-1-phosphate (S1P) receptor agonists affect T cell entry and exit from these organs. Recent developments in intravital microscopy (IVM) techniques reveal unexpected autonomous random motion of lymphocytes within secondary lymphoid tissues, and provoke questions about the mechanisms that guide their compartmental navigation.

Animals↗
PubMed2004

Effects of nurse follow-up on emergency room revisits: a randomized controlled trial.

The emergency room (ER) is the gatekeeper of the hospital. It receives clients seeking help from the health care system, then refers them for necessary further care or, discharges them back into the community. A 1-year randomized control trial was conducted in an acute general hospital in Hong Kong to see if post-ER nurse follow-up helped to change health outcome and health care utilization. The intervention group received two follow-up calls from an experienced ER nurse, within 1-2 days and 3-5 days after ER discharge. The calls' content and the management options decisions were protocol driven. A total of 795 patients (intervention group=395, control group=400) completed the study. Bivariate analysis shows two significantly different variables between the intervention and control groups, improvement of the condition and ER revisit within 30 days. When other factors are controlled in a multivariate analysis using logistic regression, the effect of the intervention on re-visits to ER within 30 days is reversed. Gender, times of attending general practitioner after ER visits, and not considering other doctors are risks factors related to a higher chance of re-visiting ER within 30 days. Those who have an improved health condition and higher number of times attending general outpatient after ER visits are associated with a lower 30-day ER revisit rate. Nurse telephone follow-ups might have sensitized subjects to health care needs. Some subjects tended to use the ER as a primary care setting and some were doctor-shoppers. A more structured ER transitional model that incoporates nurse telephone follow-up and better interfacing between private and public health care sector, primary and tertiary care might help to decrease inappropriate ER use.

Aftercare↗
PubMed2004

The genetics of autoimmune thyroid disease.

Autoimmune thyroid diseases (AITDs), such as Graves' hyperthyroidism, are common disorders involving multiple genes and the environment. Some pathogenetic genes are probably shared between these diseases and non-endocrine autoimmune diseases, whereas others are disease specific. Population studies show that major histocompatibility complex alleles and CTLA4 confer risk for AITDs. Genetic studies have identified over 20 potential loci; only one, mapping to 5q31, has been convincingly replicated. Despite its recent emergence as an autoimmunity gatekeeper gene, linkage of CLTA4 to AITDs was described in only one Caucasian population subset. Like in the case of many complex genetic disorders, identifying AITD pathogenetic genes is limited by the ability of data analysis methods to discern the influence of genes of minor effect in a relatively small database.

Autoimmune Diseases↗
PubMed2004

IP(3) receptors: the search for structure.

Inositol (1,4,5)-trisphosphate receptors (IP(3)R) are intracellular Ca(2+) channels that are regulated by Ca(2+) and IP(3), and are modulated by many additional signals. They thereby allow both receptors that stimulate IP(3) formation and Ca(2+) to control release of Ca(2+) from intracellular stores. IP(3)Rs share many features with their close relatives, ryanodine receptors; each provides insight into the structure and function of the other. The structural basis of IP(3)R behaviour is beginning to emerge from intermediate-resolution structures of the complete IP(3)R, a 2.2-A structure of the IP(3)-binding core and comparisons with the pore structures of other tetrameric cation channels. The binding of IP(3) to a site towards the N-terminal of each IP(3)R subunit promotes binding of Ca(2+). This destabilizes an inhibitory interaction between N-terminal residues and a C-terminal 'gatekeeper' sequence, enabling the pore to open.

Amino Acid Sequence↗
PubMed2004

Early enterocytic differentiation of HT-29 cells: biochemical changes and strength increases of adherens junctions.

We have characterized the modulation of cell-cell adhesion and the structure of adherens junctions in the human colon adenocarcinoma HT-29 cell line that differentiates into enterocytes after glucose substitution for galactose in the medium. We demonstrate that differentiated cells (HT-29 Gal) rapidly established E-cadherin-mediated interactions in aggregation assays. This effect is not due to an increase in E-cadherin expression during this early stage of cell differentiation, but rather results from the maturation of preexisting adherens junctions. These junctions are characterized by the redistribution of E-cadherin to the basolateral membrane and its co-localization with the actin cytoskeleton. Subcellular fractionation studies indicate that actin-associated E-cadherins bind beta-catenin and p120ctn. Furthermore, the p120ctn/E-cadherin association is upregulated. These data reveal a cooperative interaction between p120ctn and E-cadherin that corresponds to mature functional adherens junctions able to initiate tight cell-cell adhesion required for epithelium architecture and further affirm the gatekeeper role of p120ctn.

Actins↗