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1.
BMC Health Serv Res ; 18(1): 376, 2018 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-29793473

RESUMEN

BACKGROUND: Eldercare and care of people with functional impairments is organized by the municipalities in Sweden. Improving care in these areas is complex, with multiple stakeholders and organizations. Appropriate strategies to develop capability for continuing organizational improvement and learning (COIL) are needed. The purpose of our study was to develop and pilot-test a flexible, multilevel approach for COIL capability building and to identify what it takes to achieve changes in key actors' approaches to COIL. The approach, named "Sustainable Improvement and Development through Strategic and Systematic Approaches" (SIDSSA), was applied through an action-research and action-learning intervention. METHODS: The SIDSSA approach was tested in a regional research and development (R&D) unit, and in two municipalities handling care of the elderly and people with functional impairments. Our approach included a multilevel strategy, development loops of five flexible phases, and an action-learning loop. The approach was designed to support systems understanding, strategic focus, methodological practices, and change process knowledge - all of which required double-loop learning. Multiple qualitative methods, i.e., repeated interviews, process diaries, and documents, provided data for conventional content analyses. RESULTS: The new approach was successfully tested on all cases and adopted and sustained by the R&D unit. Participants reported new insights and skills. The development loop facilitated a sense of coherence and control during uncertainty, improved planning and problem analysis, enhanced mapping of context and conditions, and supported problem-solving at both the individual and unit levels. The systems-level view and structured approach helped participants to explain, motivate, and implement change initiatives, especially after working more systematically with mapping, analyses, and goal setting. CONCLUSIONS: An easily understood and generalizable model internalized by key organizational actors is an important step before more complex development models can be implemented. SIDSSA facilitated individual and group learning through action-learning and supported systems-level views and structured approaches across multiple organizational levels. Active involvement of diverse organizational functions and levels in the learning process was facilitated. However, the time frame was too short to fully test all aspects of the approach, specifically in reaching beyond the involved managers to front-line staff and patients.


Asunto(s)
Atención a la Salud/organización & administración , Servicios de Salud para Ancianos/organización & administración , Mejoramiento de la Calidad , Desarrollo de Personal , Anciano , Personas con Discapacidad , Investigación sobre Servicios de Salud , Humanos , Aprendizaje , Proyectos Piloto , Suecia
2.
Ann Oncol ; 28(7): 1631-1639, 2017 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-28475671

RESUMEN

BACKGROUND: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. PATIENTS AND METHODS: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. RESULTS: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. CONCLUSIONS: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Imidazoles/administración & dosificación , Melanoma/tratamiento farmacológico , Mutación , Oximas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/genética , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Método Doble Ciego , Esquema de Medicación , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Estimación de Kaplan-Meier , Melanoma/genética , Melanoma/mortalidad , Melanoma/secundario , Oximas/efectos adversos , Oximas/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Piridonas/efectos adversos , Piridonas/farmacocinética , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinética , Factores de Riesgo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Factores de Tiempo , Resultado del Tratamiento
3.
J Eur Acad Dermatol Venereol ; 31(4): 603-615, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27580240

RESUMEN

There is limited comparative evidence of the outcomes of different types of surgical management in patients with malignant melanoma in Europe. To address that gap we conducted a systematic literature review to summarize studies reporting outcomes of surgical procedures in patients with malignant melanoma in Europe. Medline was searched for European studies published in English, between 2004 and 2014 reporting surgical outcomes in adults with cutaneous malignant melanoma. We identified 23 studies that evaluated 18 332 patients treated surgically between 1979 and 2009 from 11 European countries. Most of the studies (21/23) were observational; the two remaining studies were randomized controlled trials (RCTs). Studies compared the effect of a range of surgical interventions on a range of clinical outcomes, more commonly overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS). Wider excisions were not associated with improved survival in patients with melanoma thickness ≥2 mm in both studies (RCTs), however, recent results based on long-term follow-up data associate 3 cm excision margins (vs. 1 cm) with favourable survival outcomes. There was some evidence that complete lymph node dissection after positive sentinel lymph node offers survival benefits over therapeutic lymph node dissection. Sentinel lymph node biopsy was not shown to be associated with significant OS benefits, however, it was overly related with higher rates of DFS/RFS. This review highlights the difficulties of making comparisons between different types of surgical procedures for malignant melanoma. As surgery remains the main treatment, this is an important field, and further evidence, particularly from RCTs, is needed.


Asunto(s)
Escisión del Ganglio Linfático , Melanoma/cirugía , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Supervivencia sin Enfermedad , Europa (Continente) , Humanos , Metástasis Linfática , Márgenes de Escisión , Melanoma/secundario , Ganglio Linfático Centinela/patología , Ganglio Linfático Centinela/cirugía , Biopsia del Ganglio Linfático Centinela , Tasa de Supervivencia , Resultado del Tratamiento , Carga Tumoral
4.
Br J Dermatol ; 172(3): 700-6, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25323770

RESUMEN

BACKGROUND: Both patient survival and the proportion of patients diagnosed with thin cutaneous malignant melanoma (CMM) have been steadily rising in Sweden as in most Western countries, although the rate of improvement in survival appears to have declined in Sweden at the end of the last millennium. OBJECTIVES: To analyse the most recent trends in the distribution of tumour thickness (T category) as well as CMM-specific survival in Swedish patients diagnosed during 1997-2011. METHODS: This nationwide population-based study included 30,590 patients registered in the Swedish Melanoma Register (SMR) and diagnosed with a first primary invasive CMM during 1997-2011. The patients were followed through 2012 in the national Cause of Death Register. RESULTS: Logistic and Cox regression analyses adjusting for age at diagnosis, tumour site and healthcare region were carried out. The odds ratio for being diagnosed with thicker tumours was significantly reduced (P < 0·001) and the CMM-specific survival significantly improved in men diagnosed during 2007-2011 compared with men diagnosed during 1997-2001 (hazard ratio = 0·81; 95% confidence interval 0·72-0·91; P < 0·001), while the corresponding differences for women were not significant. Women were diagnosed with significantly thicker tumours during 2002-2006 and a tendency towards decreased survival was observed compared with those diagnosed earlier (during 1997-2001) and later (during 2007-2011). CONCLUSIONS: In Sweden, the CMMs of men are detected earlier over time and this seems to be followed by an improved CMM-specific survival for men. Women are still diagnosed with considerably thinner tumours and they experience a better survival than men.


Asunto(s)
Melanoma/mortalidad , Neoplasias Cutáneas/mortalidad , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Melanoma/patología , Persona de Mediana Edad , Mortalidad/tendencias , Neoplasias Cutáneas/patología , Suecia/epidemiología , Melanoma Cutáneo Maligno
5.
Br J Dermatol ; 172(1): 175-86, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24910143

RESUMEN

BACKGROUND: The prognostic impact of several histopathological prognostic features in cutaneous malignant melanoma (CMM) remains controversial. OBJECTIVES: To assess the independent prognostic value of mitotic rate, regression, tumour-infiltrating lymphocytes (TILs) and growth phase in primary stage I and II CMMs. METHODS: Clinicohistopathological data were obtained from the Stockholm-Gotland registry for 4237 patients diagnosed with an incident primary stage I or II CMM followed up to December 2011. The risk of CMM-specific death was evaluated by a Cox regression model. RESULTS: A mitotic rate of 1-10 mitoses per mm(2) [hazard ratio (HR) 1·69, 95% confidence interval (CI) 1·16-2·45] and > 10 mitoses per mm(2) (HR 2·27, 95% CI 1·46-3·52) were significant; TILs and regression were not. A more detailed analysis of data assessed between 1989 and 1995 confirmed significantly increased HRs for the presence vs. absence of mitoses (HR1-5/mm² 2·25, 95% CI 1·36-3·76; HR6-10/mm² 2·34, 95% CI 1·23-4·44; HR> 10/mm² 2·64, 95% CI 1·39-4·99). Other prognosticators were increasing T-stage vs. T1, presence of ulceration and presence of vertical growth phase (VGP). In T1 CMMs, an increasing tumour thickness vs. < 0·7 mm (HR0·7-0·8 mm 2·24, 95% CI 1·24-4·04; HR>0·8 mm  2·92, 95% CI 1·57-5·43) and presence of ulceration were significantly associated with higher HRs; mitotic rate, TILs, regression and growth phase were not. CONCLUSIONS: Determinants of increased risk of CMM death in stage I and II CMMs were increasing T-stage, presence of ulceration, presence of mitoses and VGP. This was not found for TILs or regression.


Asunto(s)
Melanoma/mortalidad , Neoplasias Cutáneas/mortalidad , Adolescente , Adulto , Distribución por Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Métodos Epidemiológicos , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Pronóstico , Distribución por Sexo , Neoplasias Cutáneas/patología , Suecia/epidemiología , Adulto Joven , Melanoma Cutáneo Maligno
6.
Br J Cancer ; 110(10): 2489-95, 2014 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-24722184

RESUMEN

BACKGROUND: Disseminated cutaneous malignant melanoma (CMM) is commonly unresponsive to standard chemotherapies, and there are as yet no predictive markers of therapy response. METHODS: In the present study we collected fresh-frozen pretreatment lymph-node metastasis samples (n=14) from melanoma patients with differential response to dacarbazine (DTIC) or temozolomide (TMZ) chemotherapy, to identify proteins with an impact on treatment response. We performed quantitative protein profiling using tandem mass spectrometry and compared the proteome differences between responders (R) and non-responders (NR), matched for age, gender and histopathological type of CMM. RESULTS: Biological pathway analyses showed several signalling pathways differing between R vs NR, including Rho signalling. Gene expression profiling data was available for a subset of the samples, and the results were compared with the proteomics data. Four proteins with differential expression between R and NR were selected for technical validation by immunoblotting (ISYNA1, F13A1, CSTB and S100A13), and CSTB and S100A13 were further validated on a larger sample set by immunohistochemistry (n=48). The calcium binding protein S100A13 was found to be significantly overexpressed in NR compared with R in all analyses performed. CONCLUSIONS: Our results suggest that S100A13 is involved in CMM resistance to DTIC/TMZ.


Asunto(s)
Antineoplásicos/farmacología , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Resistencia a Antineoplásicos/fisiología , Metástasis Linfática , Melanoma/secundario , Proteínas de Neoplasias/fisiología , Proteómica/métodos , Proteínas S100/fisiología , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Cistatina B/biosíntesis , Cistatina B/genética , Dacarbazina/uso terapéutico , Factor XIII/biosíntesis , Factor XIII/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Persona de Mediana Edad , Mio-Inositol-1-Fosfato Sintasa/biosíntesis , Mio-Inositol-1-Fosfato Sintasa/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Estudios Prospectivos , Proteínas S100/biosíntesis , Proteínas S100/genética , Neoplasias Cutáneas/patología , Espectrometría de Masas en Tándem , Temozolomida , Adulto Joven , Melanoma Cutáneo Maligno
8.
J Intern Med ; 276(1): 87-95, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24548296

RESUMEN

BACKGROUND: Snus is a moist smokeless tobacco product with high nicotine content. Its use has a short-term effect on the cardiovascular system, but the relationship between snus use and stroke is unclear. OBJECTIVE: The aim of this study was to assess the associations between use of snus and incidence of and survival after stroke, both overall and according to subtypes. METHODS: Pooled analyses of eight Swedish prospective cohort studies were conducted, including 130 485 men who never smoked. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of incidence and death after diagnosis using Cox proportional hazard regression models and case fatality and survival using logistic regression and Kaplan-Meier methods, respectively. RESULTS: No associations were observed between the use of snus and the risk of overall stroke (HR 1.04, 95% CI 0.92-1.17) or of any of the stroke subtypes. The odds ratio (OR) of 28-day case fatality was 1.42 (95% CI 0.99-2.04) amongst users of snus who had experienced a stroke, and the HR of death during the follow-up period was 1.32 (95% CI 1.08-1.61). CONCLUSION: Use of snus was not associated with the risk of stroke. Hence, nicotine is unlikely to contribute importantly to the pathophysiology of stroke. However, case fatality was increased in snus users, compared with nonusers, but further studies are needed to determine any possible causal mechanisms.


Asunto(s)
Accidente Cerebrovascular/mortalidad , Tabaco sin Humo/efectos adversos , Adulto , Anciano , Métodos Epidemiológicos , Estimulantes Ganglionares/efectos adversos , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Nicotina/efectos adversos , Agonistas Nicotínicos/efectos adversos , Accidente Cerebrovascular/etiología , Suecia/epidemiología
9.
Br J Cancer ; 109(3): 559-64, 2013 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-23860532

RESUMEN

BACKGROUND: Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas. The aim was to determine the KIT, NRAS and BRAF mutation frequencies in a large series of primary SNMMs. METHODS: Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing. RESULTS: Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56), whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1. Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity (P=0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than those with tumours in the paranasal sinuses (P=0.027). CONCLUSION: Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour alterations in genes other than KIT, NRAS and BRAF.


Asunto(s)
GTP Fosfohidrolasas/genética , Melanoma/genética , Proteínas de la Membrana/genética , Mutación , Neoplasias de los Senos Paranasales/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-kit/genética , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Captura por Microdisección con Láser , Masculino , Melanoma/patología , Persona de Mediana Edad , Adhesión en Parafina , Tasa de Supervivencia
10.
Br J Dermatol ; 168(4): 779-86, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23066913

RESUMEN

BACKGROUND: Survival and prognostic factors for thin melanomas have been studied relatively little in population-based settings. This patient group accounts for the majority of melanomas diagnosed in western countries today, and better prognostic information is needed. OBJECTIVES: The aim of this study was to use established prognostic factors such as ulceration, tumour thickness and Clark's level of invasion for risk stratification of T1 cutaneous melanoma. METHODS: From 1990 to 2008, the Swedish Melanoma Register included 97% of all melanomas diagnosed in Sweden. Altogether, 13,026 patients with T1 melanomas in clinical stage I were used for estimating melanoma-specific 10- and 15-year mortality rates. The Cox regression model was used for further survival analysis on 11,165 patients with complete data. RESULTS: Ulceration, tumour thickness and Clark's level of invasion all showed significant, independent, long-term prognostic information. By combining these factors the patients could be subdivided into three risk groups: a low-risk group (67·9% of T1 cases) with a 10-year melanoma-specific mortality rate of 1·5% (1·2-1·9%); an intermediate-risk group (28·6% of T1 cases) with a 10-year mortality rate of 6·1% (5·0-7·3%); and a high-risk group (3·5% of T1 cases) with a 10-year mortality rate of 15·6% (11·2-21·4%). The high- and intermediate-risk groups accounted for 66% of melanoma deaths within T1. CONCLUSIONS: Using a population-based melanoma register, and combining ulceration, tumour thickness and Clark's level of invasion, three distinct prognostic subgroups were identified.


Asunto(s)
Melanoma/mortalidad , Neoplasias Cutáneas/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Melanoma/patología , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Estudios Prospectivos , Sistema de Registros , Neoplasias Cutáneas/patología , Úlcera Cutánea/mortalidad , Úlcera Cutánea/patología , Tasa de Supervivencia , Suecia/epidemiología , Adulto Joven
11.
Rhinology ; 51(1): 22-30, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23441308

RESUMEN

OBJECTIVE: To establish population-based trends for sinonasal mucosal melanoma (SNMM) in Sweden. METHODS: We identified 186 patients from the Swedish National Cancer Registry diagnosed with primary melanomas arising from the nasal cavity, paranasal sinuses, or both, during the period 1960 through 2000. Incidence, gender and age, primary anatomical sites, geographic distribution, treatment and survival were investigated. RESULTS: The age-standardized incidence of SNMM increased significantly during the 41-year-period, with a higher overall incidence for females than males, but with a more rapid increase for males than for females. The incidence increased with age, peaking after the eightieth year in both genders. About 70 % of the cases were clinically amelanotic. The most common primary treatment was surgery. Five-year, disease-specific survival rates were poor for all these patients, but women had a significantly better survival time than men. For both genders the survival rate lengthened during the study period, irrespective of therapeutic strategy. CONCLUSION: SNMM is a rare disease, but the incidence in Sweden has increased significantly from 1960 through 2000, although not at the same pace as that of cutaneous malignant melanoma. Both the incidence and the survival were significantly higher in females than in males, but the reason for these gender differences is unknown.


Asunto(s)
Melanoma/epidemiología , Neoplasias Nasales/epidemiología , Neoplasias de los Senos Paranasales/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Sistema de Registros , Factores Sexuales , Tasa de Supervivencia , Suecia/epidemiología
12.
Nat Genet ; 11(1): 76-82, 1995 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-7550319

RESUMEN

Sensitivity of blood pressure to dietary salt is a common feature in subjects with hypertension. These features are exemplified by the mendelian disorder, Liddle's syndrome, previously shown to arise from constitutive activation of the renal epithelial sodium channel due to mutation in the beta subunit of this channel. We now demonstrate that this disease can also result from a mutation truncating the carboxy terminus of the gamma subunit of this channel; this truncated subunit also activates channel activity. These findings demonstrate genetic heterogeneity of Liddle's syndrome, indicate independent roles of beta and gamma subunits in the negative regulation of channel activity, and identify a new gene in which mutation causes a salt-sensitive form of human hypertension.


Asunto(s)
Hipertensión/genética , Activación del Canal Iónico/genética , Canales de Sodio/genética , Sodio en la Dieta/efectos adversos , Adolescente , Adulto , Aldosterona/deficiencia , Alelos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Codón/genética , Canales Epiteliales de Sodio , Regulación de la Expresión Génica , Genes , Genes Dominantes , Humanos , Hipertensión/inducido químicamente , Hipertensión/clasificación , Hipertensión/metabolismo , Hipopotasemia/genética , Túbulos Renales Proximales/metabolismo , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mutación , Oocitos/metabolismo , Linaje , Ratas , Proteínas Recombinantes de Fusión/metabolismo , Renina/deficiencia , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Canales de Sodio/deficiencia , Canales de Sodio/fisiología , Síndrome , Regiones Terminadoras Genéticas , Xenopus laevis
14.
Redox Biol ; 53: 102343, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35640380

RESUMEN

Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behavior in normal and malignant hematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4,438 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenic changes to oxidation state of thiols in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified oxidation changes to thiols acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signaling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukemia.


Asunto(s)
Proteoma , Proteómica , Animales , Cisteína/metabolismo , Hematopoyesis , Ratones , Oxidación-Reducción , Proteoma/metabolismo , Compuestos de Sulfhidrilo
15.
J Exp Med ; 180(6): 2371-6, 1994 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-7964510

RESUMEN

Interleukin 10 (IL-10) is a cytokine with a variety of reported effects including inhibition of monocyte major histocompatibility complex (MHC) class II-dependent antigen presentation, type 1 helper T cell cytokine production, and inhibition of T cell proliferation. Herein we report the effect of IL-10 pretreatment on antigen presentation to tumor- and allo-specific CD8+ cytotoxic T lymphocytes (CTL). Prior incubation of human melanoma cells with recombinant IL-10 (rIL-10) for 48-72 h resulted in a dose-dependent, up to 100% inhibition, of autologous CTL-mediated, HLA-A2.1-restricted, tumor-specific lysis. Allo-specific CTL cytotoxicity against Epstein-Barr virus-transformed lymphoblastoid cell lines (LCL) was also inhibited, demonstrating a protective effect also on lymphoid cells. In contrast, IL-10 pretreatment of allogeneic LCL or K562 targets had either no effect or slightly enhanced cytotoxic activity mediated by freshly isolated or IL-2-activated natural killer cells. Flow cytometric analysis with monoclonal antibodies against HLA-A2, or nonpolymorphic determinants of MHC class I proteins, revealed a 20-50% reduction in cell-surface expression, whereas intercellular adhesion molecules 1, and 2, and lymphocyte function-associated antigen 3 levels were not affected. In addition, relative to untreated target cells, IL-10 pretreated tumor cells were unaltered in their capacity to affect CTL-mediated lysis by cold target inhibition, demonstrating that the effect of IL-10 is unrelated to the initial binding of CTL to their targets. These results are compatible with an effect of IL-10 on the MHC class I antigen presentation pathway, and suggest a novel mechanism of immune tolerance, based on escape from CTL-mediated tumor and allo-transplant rejection.


Asunto(s)
Antígenos CD , Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/biosíntesis , Interleucina-10/farmacología , Melanoma/inmunología , Linfocitos T Citotóxicos/inmunología , Anticuerpos Monoclonales , Linfocitos T CD8-positivos/efectos de los fármacos , Moléculas de Adhesión Celular/biosíntesis , Línea Celular , Citotoxicidad Inmunológica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Antígeno HLA-A2/biosíntesis , Humanos , Molécula 1 de Adhesión Intercelular/biosíntesis , Cinética , Leucemia Eritroblástica Aguda , Ganglios Linfáticos/inmunología , Metástasis Linfática , Proteínas Recombinantes/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Células Tumorales Cultivadas
16.
J Intern Med ; 265(6): 717-24, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19504754

RESUMEN

OBJECTIVE: To study the association between snus use and the risk for cardiovascular disease, i.e. ischemic heart disease and stroke. DESIGN: Cohort study. SETTING: Sweden. SUBJECTS: Sixteen thousand six hundred and forty-two male Swedish twins participating in the Screening Across the Lifespan Twin Study, conducted in 1998- 2002, were followed for incident cardiovascular disease. Participants were without a history of cardiovascular disease at baseline and incident cases were identified via the Swedish Cause of Death Register and Hospital Discharge Register. RESULTS: Overall, there was no association between use of snus and risk for cardiovascular disease. Current snus users, without a smoking history, had a relative risk of 1.00 (95% confidence interval 0.69-1.46) for cardiovascular disease as compared to non users. Corresponding relative risks for ischemic heart disease and stroke were 0.85 (95% confidence interval 0.51-1.41) and 1.18 (95% confidence interval 0.67-2.08), respectively. In smoking adjusted models, risk estimates for ischemic heart disease in relation to snus use were all close to unity regardless of timing or intensity of snus use. However, current heavy snus users (consuming more than four cans week(-1)) had a relative risk for stroke of 1.75 (95% confidence interval 0.95-3.21). CONCLUSION: These data do not support any strong association between snus use and risk for cardiovascular disease.


Asunto(s)
Enfermedades Cardiovasculares/etiología , Tabaquismo/complicaciones , Tabaco sin Humo/efectos adversos , Adulto , Enfermedades Cardiovasculares/epidemiología , Estudios de Cohortes , Estudios de Seguimiento , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Suecia/epidemiología , Tabaquismo/epidemiología
17.
Br J Surg ; 96(5): 473-81, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19358184

RESUMEN

BACKGROUND: A trial in selected men suggested that antibiotic therapy could be an alternative to appendicectomy in appendicitis. This study aimed to evaluate antibiotic therapy in unselected men and women with acute appendicitis. METHODS: Consecutive patients were allocated to study (antibiotics) or control (surgery) groups according to date of birth. Study patients received intravenous antibiotics for 24 h and continued at home with oral antibiotics for 10 days. Control patients had a standard appendicectomy. Follow-up at 1 and 12 months was carried out according to intention and per protocol. RESULTS: Study and control patients were comparable at inclusion; 106 (52.5 per cent) of 202 patients allocated to antibiotics completed the treatment and 154 (92.2 per cent) of 167 patients allocated to appendicectomy had surgery. Treatment efficacy was 90.8 per cent for antibiotic therapy and 89.2 per cent for surgery. Recurrent appendicitis occurred in 15 patients (13.9 per cent) after a median of 1 year. A third of recurrences appeared within 10 days and two-thirds between 3 and 16 months after hospital discharge. Minor complications were similar between the groups. Major complications were threefold higher in patients who had an appendicectomy (P < 0.050). CONCLUSION: Antibiotic treatment appears to be a safe first-line therapy in unselected patients with acute appendicitis. REGISTRATION NUMBER: NCT00469430 (http://www.clinicaltrials.gov).


Asunto(s)
Antibacterianos/administración & dosificación , Apendicectomía , Apendicitis/tratamiento farmacológico , Complicaciones Posoperatorias/etiología , Dolor Abdominal/etiología , Enfermedad Aguda , Administración Oral , Adulto , Antibacterianos/efectos adversos , Apendicitis/cirugía , Costos y Análisis de Costo , Femenino , Humanos , Infusiones Intravenosas , Tiempo de Internación , Masculino , Estudios Prospectivos , Prevención Secundaria , Ausencia por Enfermedad , Resultado del Tratamiento
18.
Med Hypotheses ; 131: 109307, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31443755

RESUMEN

The function of sleep in mammal and other vertebrates is one of the great mysteries of biology. Many hypotheses have been proposed, but few of these have made even the slightest attempt to explain the essence of sleep - the uncompromising need for reversible unconsciousness. During sleep, epiphenomena - often of a somatic character - occur, but these cannot explain the core function of sleep. One answer could be hidden in the observations made for long periods of time of the function of the central nervous system (CNS). The CNS is faced with conflicting requirements on stability and excitability. A high level of excitability is desirable, and is also a prerequisite for sensitivity and quick reaction times; however, it can also lead to instability and the risk of feedback, with life-threatening epileptic seizures. Activity-dependent negative feedback in neuronal excitability improves stability in the short term, but not to the degree that is required. A hypothesis is presented here demonstrating how calibration of individual neurons - an activity which occurs only during sleep - can establish the balanced and highest possible excitability while also preserving stability in the CNS. One example of a possible mechanism is the observation of slow oscillations in EEGs made on birds and mammals during slow wave sleep. Calibration to a genetically determined level of excitability could take place in individual neurons during the slow oscillation. This is only possible offline, which explains the need for sleep. The hypothesis can explain phenomena such as the need for unconsciousness during sleep, with the disconnection of sensory stimuli, slow EEG oscillations, the relationship of sleep and epilepsy, age, the effects of sleep on neuronal firing rate and the effects of sleep deprivation and sleep homeostasis. This is with regard primarily to mammals, including humans, but also all other vertebrates.


Asunto(s)
Cognición/fisiología , Modelos Neurológicos , Neuronas/fisiología , Sueño/fisiología , Potenciales de Acción , Animales , Evolución Biológica , Ondas Encefálicas/fisiología , Sistema Nervioso Central/fisiología , Ritmo Circadiano/fisiología , Electroencefalografía , Humanos , Memoria/fisiología , Plasticidad Neuronal , Sinapsis/fisiología , Vertebrados/fisiología
19.
Radiography (Lond) ; 25 Suppl 1: S14-S18, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31481182

RESUMEN

INTRODUCTION: Radiographers routinely undertake many initiatives to balance image quality with radiation dose (optimisation). For optimisation studies to be successful image quality needs to be carefully evaluated. Purpose was to 1) discuss the strengths and limitations of a Visual Grading Analysis (VGA) method for image quality evaluation and 2) to outline the method from a radiographer's perspective. METHODS: A possible method for investigating and discussing the relationship between radiographic image quality parameters and the interpretation and perception of X-ray images is the VGA method. VGA has a number of advantages such as being low cost and a detailed image quality assessment, although it is limited to ensure the images convey the relevant clinical information and relate the task based radiography. RESULTS: Comparing the experience of using VGA and Receiver Operating Characteristic (ROC) it is obviously that less papers are published on VGA (Pubmed n=1.384) compared to ROC (Pubmed n=122.686). Hereby the scientific experience of the VGA method is limited compared to the use of ROC. VGA is, however, a much newer method and it is slowly gaining more and more attention. CONCLUSION: The success of VGA requires a number of steps to be completed, such as defining the VGA criteria, choosing the VGA method (absolute or relative), including observers, finding the best image display platforms, training observers and selecting the best statistical method for the study purpose should be thoroughly considered. IMPLICATION FOR PRACTICE: Detailed evaluation of image quality for optimisation studies related to technical definition of image quality.


Asunto(s)
Intensificación de Imagen Radiográfica/métodos , Radiografía/normas , Interpretación Estadística de Datos , Humanos , Variaciones Dependientes del Observador , Curva ROC , Radiografía/métodos , Radiografía/estadística & datos numéricos
20.
Acta Radiol ; 49(4): 468-74, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18415793

RESUMEN

BACKGROUND: Recently, the dual-side readout technique has been introduced in computed radiography, leading to an increase in detective quantum efficiency (DQE) compared with the single-side readout technique. PURPOSE: To evaluate if the increase in DQE with the dual-side readout technique results in a higher clinical image quality in chest radiography of premature neonates at no increase in radiation dose. MATERIAL AND METHODS: Twenty-four chest radiographs of premature neonates were collected from both a single-side readout technique system and a double-side readout technique system. The images were processed in the same image-processing station in order for the comparison to be only dependent on the difference in readout technique. Five radiologists rated the fulfillment of four image quality criteria, which were based on important anatomical landmarks. The given ratings were analyzed using visual grading characteristics (VGC) analysis. RESULTS: The VGC analysis showed that the reproduction of the carina with the main bronchi and the thoracic vertebrae behind the heart was better with the dual-side readout technique, whereas no significant difference for the reproduction of the central vessels or the peripheral vessels could be observed. CONCLUSIONS: The results indicate that the higher DQE of the dual-side readout technique leads to higher clinical image quality in chest radiography of premature neonates at no increase in radiation dose.


Asunto(s)
Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Radiografía Torácica/métodos , Área Bajo la Curva , Humanos , Recién Nacido , Recien Nacido Prematuro , Dosis de Radiación , Estudios Retrospectivos , Programas Informáticos
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