L'Envelliment, aproximació a un procés complex i heterogeni

L'envelliment és un procés complex i heterogeni, no tots envellim de la mateixa manera. En els últims anys s'han incorporat nous conceptes clínics i biològics que poden arribar a qüestionar la natura fisiològica del procés. En aquest capítol es defineix el procés i la seva repercussió en la nostra societat, s'incorporen conceptes com ara la fragilitat, la comorbiditat o la discapacitat, que permeten entendre millor i més bé les repercussions de l'envelliment sobre el nostre organisme, i s'analitzen les peculiaritats dels que envelleixen de manera satisfactòria i arriben a centenaris. Es discuteix el concepte anti-aging des d'una vessant científica i analitzant altres connotacions del concepte. Finalment, s'intenta relacionar l'envelliment del sistema immunitari (immunosenescència) amb algunes malalties autoimmunitàries sistèmiques com ara l'esclerodèrmia i l'arteritis de cèŀlules gegants, i es comenta la progèria i les síndromes progeroides com a models d'estudi de l'envelliment.Aging is a complex and heterogeneous process, with relevant differences between subjects. Conceptual, clinic and biological concepts which can challenge the physiologic nature of aging have been incorporated during the last years. In this chapter a proper definition of aging and the social repercussion of the phenomenon is established, and new concepts such as fragility, comorbidity and discapacity which allow a better understanding of aging and related pathology are described. Centenarians and its rationale is also discussed and analyzed, along with the anti-aging phenomenon and its repercussions on agining. Lastly, a possible relationship between some autoimmune systemic diseases such as systemic sclerosis and giant cell vasculitis (Horton’s disease) and immunosenescence, and also the progeroid syndromes as a model of aging are addressed

Efficacy and safety of lenalidomide for refractory cutaneous lupus erythematosus

Introduction: Cutaneous lupus erythematosus (CLE) is a chronic disease characterized by disfigurement and a relapsing course. Thalidomide has proven its efficacy in refractory cutaneous lupus disease, although it is not exempt from significant side effects and frequent relapses after withdrawal. New thalidomide analogues have been developed but lack clinical experience. The aim of this preliminary phase II study was to evaluate the efficacy and safety of lenalidomide in patients with refractory CLE. Methods: Fifteen patients with refractory cutaneous lupus disease were enrolled in this single-center, open-label, non-comparative pilot trial between January 2009 and December 2010. Oral lenalidomide (5 to 10 mg/day) was administered and tapered according to clinical response. Patients were followed up for a mean of 15 months (range: 7 to 30). Primary efficacy endpoint was the proportion of patients achieving complete response, defined by a Cutaneous Lupus Erythematosus Disease Area and Severity index (CLASI) activity score of 0. Other secondary endpoints included development of side effects, evaluation of cutaneous and systemic flares, and impact on the immunological parameters.Results: One patient discontinued treatment due to side effects. All remaining patients saw clinical improvement and this was already noticeable after 2 weeks of treatment. Twelve of those patients (86%) achieved complete response but clinical relapse was frequent (75%), usually occurring 2 to 8 weeks after lenalidomide's withdrawal. No influence on systemic disease, immunological parameters or CLASI damage score was observed. Side effects including insomnia, grade 2 neutropenia and gastrointestinal symptoms, were minor (13%). These resolved after withdrawing medication. Neither polyneuropathy nor thrombosis was observed. Conclusion: Lenalidomide appears to be efficacious and safe in patients with refractory CLE, but clinical relapse is frequent after its withdrawal

L'Envelliment, aproximació a un procés complex i heterogeni

L'envelliment és un procés complex i heterogeni, no tots envellim de la mateixa manera. En els últims anys s'han incorporat nous conceptes clínics i biològics que poden arribar a qüestionar la natura fisiològica del procés. En aquest capítol es defineix el procés i la seva repercussió en la nostra societat, s'incorporen conceptes com ara la fragilitat, la comorbiditat o la discapacitat, que permeten entendre millor i més bé les repercussions de l'envelliment sobre el nostre organisme, i s'analitzen les peculiaritats dels que envelleixen de manera satisfactòria i arriben a centenaris. Es discuteix el concepte anti-aging des d'una vessant científica i analitzant altres connotacions del concepte. Finalment, s'intenta relacionar l'envelliment del sistema immunitari (immunosenescència) amb algunes malalties autoimmunitàries sistèmiques com ara l'esclerodèrmia i l'arteritis de cèŀlules gegants, i es comenta la progèria i les síndromes progeroides com a models d'estudi de l'envelliment.Aging is a complex and heterogeneous process, with relevant differences between subjects. Conceptual, clinic and biological concepts which can challenge the physiologic nature of aging have been incorporated during the last years. In this chapter a proper definition of aging and the social repercussion of the phenomenon is established, and new concepts such as fragility, comorbidity and discapacity which allow a better understanding of aging and related pathology are described. Centenarians and its rationale is also discussed and analyzed, along with the anti-aging henomenon and its repercussions on agining. Lastly, a possible relationship between some autoimmune systemic diseases such as systemic sclerosis and giant cell vasculitis (Hortons disease) and immunosenescence, and also the progeroid syndromes as a model of aging are addressed

Efficacy and safety of lenalidomide for refractory cutaneous lupus erythematosus

Introduction: Cutaneous lupus erythematosus (CLE) is a chronic disease characterized by disfigurement and a relapsing course. Thalidomide has proven its efficacy in refractory cutaneous lupus disease, although it is not exempt from significant side effects and frequent relapses after withdrawal. New thalidomide analogues have been developed but lack clinical experience. The aim of this preliminary phase II study was to evaluate the efficacy and safety of lenalidomide in patients with refractory CLE. Methods: Fifteen patients with refractory cutaneous lupus disease were enrolled in this single-center, open-label, non-comparative pilot trial between January 2009 and December 2010. Oral lenalidomide (5 to 10 mg/day) was administered and tapered according to clinical response. Patients were followed up for a mean of 15 months (range: 7 to 30). Primary efficacy endpoint was the proportion of patients achieving complete response, defined by a Cutaneous Lupus Erythematosus Disease Area and Severity index (CLASI) activity score of 0. Other secondary endpoints included development of side effects, evaluation of cutaneous and systemic flares, and impact on the immunological parameters.Results: One patient discontinued treatment due to side effects. All remaining patients saw clinical improvement and this was already noticeable after 2 weeks of treatment. Twelve of those patients (86%) achieved complete response but clinical relapse was frequent (75%), usually occurring 2 to 8 weeks after lenalidomide's withdrawal. No influence on systemic disease, immunological parameters or CLASI damage score was observed. Side effects including insomnia, grade 2 neutropenia and gastrointestinal symptoms, were minor (13%). These resolved after withdrawing medication. Neither polyneuropathy nor thrombosis was observed. Conclusion: Lenalidomide appears to be efficacious and safe in patients with refractory CLE, but clinical relapse is frequent after its withdrawal

Factores predictores del deterioro funcional geriátrico

Objetivo. Demostrar la utilidad de sencillos instrumentos geriátricos como predictores del deterioro de las actividades básicas de la vida diaria (ABVD) o pérdida de calidad de vida al año en ancianos con un estado de salud previo aparentemente bueno, para poder ser aplicado en atención primaria de la salud (APS). Diseño. Estudio prospectivo. Emplazamiento. Centro de atención primaria urbano. Participantes. Muestra sistemática de 100 ancianos con edad >= 75 años, índice de Barthel (IB) >= 90, escala de Karnofsky (EK) >= 70 y ausencia de proceso neoplásico. Mediciones principales. Se les aplicó un protocolo de valoración geriátrica integral que incluía variables biopsicosociales y funcionales. Tras 12 meses se revaloraron las ABVD (IB) y la calidad de vida (EK). Se realizó la estimación de las odds ratio (OR) de asociación mediante modelos de regresión logística múltiples. Resultados. Las alteraciones en las pruebas de cognición (test de Pfeiffer > 2) y en las actividades instrumentales de la vida diaria (AIVD) (índice de Lawton [IL] < 7) se mostraron predictoras del deterioro en las ABVD (OR = 4,66; intervalo de confiaza [IC], 1,33-16,22, y OR = 4,89; IC, 1,65-14,48, respectivamente). Las alteraciones en las AIVD (IL < 7) y las alteraciones en las pruebas de rendimiento (test de Guralnik abreviado < 4) se mostraron predictores del deterioro de la calidad de vida (OR = 4,31; IC, 1,62-11,44, y OR = 7,41; IC, 1,54-35,62, respectivamente). Conclusiones. En APS, los instrumentos de valoración geriátrica centrados en las AIVD, la cognición y las pruebas de rendimiento predicen el deterioro en las ABVD y en calidad de vida

Associations between the Expression of Epigenetically Regulated Genes and the Expression of DNMTs and MBDs in Systemic Lupus Erythematosus

OBJECTIVES: We determined the expression of ITGAL, PRF1, KIR2DL4, CD70, and CD40LG in patients with SLE and performed correlations with the global DNA methylation status and the levels of three DNA methylation enzymes and two methyl CpG-binding domain (MBD) proteins. PATIENTS AND METHODS: CD4(+) T cells were isolated from 35 SLE patients and 30 healthy controls. DNA deoxymethylcytosine content was measured by an enzyme-linked immunosorbent assay (ELISA). Transcript levels of ITGAL, PRF1, KIR2DL4, CD70, CD40LG, DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 were quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: SLE patients had significantly elevated transcript levels of ITGAL (18.61±22.17 vs. 7.33±9.17, p = 0.042), PRF1 (21.67±26.34 vs. 10.67±11.65, p = 0.039), and CD70 (1.45±1.63 vs. 0.67±0.28, p = 0.011). A positive correlation was observed between transcript levels of CD40LG and ITGAL (r = 0.477, p = 0.004) as well as between CD40LG and PRF1 (r = 0.557, p = 0.001). Transcript levels of KIR2DL4 were higher than controls' but it did not reach statistical significance (1.36±3.52 vs. 0.22±0.79, p = 0.560). A tight relationship with global DNA hypomethylation as well as with the expression of most of the DNA methylation-related genes was observed, especially for ITGAL, PRF1, and CD40LG. CONCLUSIONS: ITGAL, PRF1, and CD70 are overexpressed in SLE CD4(+) T cells. The tight association of CD40LG with ITGAL and PRF1 leads us to infer that it probably contributes to the pathogenesis of the disease. The apparent simultaneous regulation between their expression and the global DNA hypomethylation as well as with the transcription of many DNA methylation-related enzymes, reinforces the idea that epigenetic mechanisms are responsible for the deregulation of ITGAL, PRF1, and CD40LG

Associations between the expression of epigenetically regulated genes and the expression of DNMTs and MBDs in systemic lupus erythematosus.

OBJECTIVES: We determined the expression of ITGAL, PRF1, KIR2DL4, CD70, and CD40LG in patients with SLE and performed correlations with the global DNA methylation status and the levels of three DNA methylation enzymes and two methyl CpG-binding domain (MBD) proteins. PATIENTS AND METHODS: CD4(+) T cells were isolated from 35 SLE patients and 30 healthy controls. DNA deoxymethylcytosine content was measured by an enzyme-linked immunosorbent assay (ELISA). Transcript levels of ITGAL, PRF1, KIR2DL4, CD70, CD40LG, DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 were quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: SLE patients had significantly elevated transcript levels of ITGAL (18.61±22.17 vs. 7.33±9.17, p = 0.042), PRF1 (21.67±26.34 vs. 10.67±11.65, p = 0.039), and CD70 (1.45±1.63 vs. 0.67±0.28, p = 0.011). A positive correlation was observed between transcript levels of CD40LG and ITGAL (r = 0.477, p = 0.004) as well as between CD40LG and PRF1 (r = 0.557, p = 0.001). Transcript levels of KIR2DL4 were higher than controls' but it did not reach statistical significance (1.36±3.52 vs. 0.22±0.79, p = 0.560). A tight relationship with global DNA hypomethylation as well as with the expression of most of the DNA methylation-related genes was observed, especially for ITGAL, PRF1, and CD40LG. CONCLUSIONS: ITGAL, PRF1, and CD70 are overexpressed in SLE CD4(+) T cells. The tight association of CD40LG with ITGAL and PRF1 leads us to infer that it probably contributes to the pathogenesis of the disease. The apparent simultaneous regulation between their expression and the global DNA hypomethylation as well as with the transcription of many DNA methylation-related enzymes, reinforces the idea that epigenetic mechanisms are responsible for the deregulation of ITGAL, PRF1, and CD40LG

KIR2DL4 transcript levels of CD4⁺ T-cells are proportional to ITGAL and PRF1 mRNA levels both in the healthy control population (A) and the SLE patients group (B).

<p>KIR2DL4 transcript levels of CD4⁺ T-cells are proportional to ITGAL and PRF1 mRNA levels both in the healthy control population (A) and the SLE patients group (B).</p

Effect of the CD4+ T cell global DNA methylation status and the expression of different DNA methylation-related enzymes (DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4) on the expression of ITGAL, PRF1, KIR2DL4, CD70, and CD40LG.

<p>Statistically (or almost statistically) significant correlations are indicated by the p-value and the Spearman's rank correlation coefficient (r) highlighted in bold.</p>1<p>Correlation values were established for just the 6 patients from whom paired data were available.</p>2<p>Correlation values were established for just the 5 patients from whom paired data were available.</p