RESUMEN
OBJECTIVE: To assess the epidemiologic and economic burden of diabetes mellitus (DM) from a longitudinal population-based study. RESEARCH DESIGN AND METHODS: Lombardy Region includes 9.9 million individuals. Its DM population was identified through a data warehouse (DENALI), which matches with a probabilistic linkage demographic, clinical and economic data of different Healthcare Administrative databases. All individuals, who, during the year 2000 had an hospital discharge with a IDC-9 CM code 250.XX, and/or two consecutive prescriptions of drugs for diabetes (ATC code A10XXXX) within one year, and/or an exemption from co-payment healthcare costs specific for DM, were selected and followed up to 9 years. We calculated prevalence, mortality and healthcare costs (hospitalizations, drugs and outpatient examinations/visits) from the National Health Service's perspective. RESULTS: We identified 312,223 eligible subjects. The study population (51% male) had a mean age of 66 (from 0.03 to 105.12) years at the index date. Prevalence ranged from 0.4% among subjects aged ≤45 years to 10.1% among those >85 years old. Overall 43.4 deaths per 1,000 patients per year were estimated, significantly (p<0.001) higher in men than women. Overall, 3,315/patient-year were spent on average: hospitalizations were the cost driver (54.2% of total cost). Drugs contributed to 31.5%, outpatient claims represented 14.3% of total costs. Thirty-five percent of hospital costs were attributable to cerebro-/cardiovascular reasons, 6% to other complications of DM, and 4% to DM as a main diagnosis. Cardiovascular drugs contributed to 33.5% of total drug costs, 21.8% was attributable to class A (16.7% to class A10) and 4.3% to class B (2.4% to class B01) drugs. CONCLUSIONS: Merging different administrative databases can provide with many data from large populations observed for long time periods. DENALI shows to be an efficient instrument to obtain accurate estimates of burden of diseases such as diabetes mellitus.
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Complicaciones de la Diabetes/economía , Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus Tipo 2/economía , Diabetes Mellitus Tipo 2/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Bases de Datos Factuales , Femenino , Costos de la Atención en Salud , Humanos , Lactante , Recién Nacido , Revisión de Utilización de Seguros/economía , Italia/epidemiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
An alteration of the retinoid pathway can influence the development of uterine leiomyomas in animal models, and retinoids have shown efficacy in inhibiting the growth of this benign tumor both in vitro and in vivo. However, the underlying mechanisms and biological implications are unclear. The present study was based on the demonstration of an accumulation of full-length retinoid X receptor alpha (RXRalpha) in leiomyomas that was not associated with a modification of its gene expression. This accumulation was shown to increase the transcription of the RXR-responsive gene cellular retinoic acid binding protein II (CRABP-II) and to be linked to the cellular redistribution of the receptor and to its retarded degradation via the ubiquitin/proteasome pathway. Accordingly, treatment with a specific proteasome inhibitor but not with protease inhibitors strongly inhibited the degradation of full-length RXRalpha in cells deriving from both myometrium and leiomyoma, but the formation of RXRalpha/ubiquitin conjugates was differentially regulated between the two cell types. Moreover, full-length RXRalpha accumulated in leiomyomas was abnormally phosphorylated at serine/threonine residues relative to myometrial tissue. The ligand to RXRalpha, 9-cis-retinoic acid, induced the receptor breakdown in smooth muscle cells deriving from both normal and tumor tissue, whereas a MAPK-specific inhibitor was able to reduce RXRalpha levels only in leiomyoma cells. These results suggest that switching of the ubiquitin/proteasome-dependent degradation of RXRalpha by phosphorylation in leiomyomas may be responsible for the accumulation of the receptor and the consequent dysregulation of retinoic acid target genes. The ability of retinoids to modify this molecular alteration may be the rationale for their use in the treatment of leiomyomas.
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Regulación Neoplásica de la Expresión Génica , Leiomioma/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Procesamiento Proteico-Postraduccional , Receptor alfa X Retinoide/metabolismo , Activación Transcripcional , Neoplasias Uterinas/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Leiomioma/metabolismo , Miocitos del Músculo Liso/metabolismo , Fosforilación , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Tretinoina/farmacología , Neoplasias Uterinas/metabolismoRESUMEN
CONTEXT: Uterine leiomyomas are the most common tumors in the human female pelvis and the leading indication for pelvic surgery. The molecular causes of the disease remain unknown. OBJECTIVE: Using an oligonucleotide microarray-based hybridization analysis, we observed that a Wnt family member transcript, Wnt5b, was overexpressed in smooth muscle cells (SMC) derived from leiomyomas when compared with matched myometrial cells. Based on this finding and on previous observations, we have hypothesized that altered expression of specific Wnt family members might be involved in leiomyoma formation and/or growth. MAIN OUTCOME MEASURES: The expression patterns of two members of the Wnt pathway, Wnt5b and secreted frizzled related protein (sFRP)1, were evaluated in myometrial SMC (n = 22) and in leiomyoma cells (n = 27) by real-time quantitative PCR. In addition, regulation of expression of the two molecules was examined. RESULTS: Compared with myometrial SMC, cells derived from leiomyomas had significantly higher levels of both Wnt5b and sFRP1 transcripts. When the data were analyzed as a function of the phase of the menstrual cycle, no significant difference in sFRP1 mRNA levels could be detected, whereas levels of Wnt5b transcript were significantly higher in the secretory phase in myometrial cells. Treatment with 9-cis retinoic acid significantly inhibited Wnt5b expression in myometrial SMC but not in their leiomyoma counterparts. CONCLUSIONS: Specific Wnt signaling genes are overexpressed in leiomyoma cells. Moreover, in these cells, the regulation of Wnt5b expression by retinoids appears to be attenuated.
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Leiomioma/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Neoplasias Uterinas/metabolismo , Adulto , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Sistemas de Computación , Femenino , Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Leiomioma/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Miometrio/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/metabolismo , Transcripción Genética , Neoplasias Uterinas/genética , Proteínas WntRESUMEN
UNLABELLED: OBJECTIVE[S]: Activin A and inhibin A are growth factors expressed by human endometrium involved in the control of endometrial functions. In the present study we investigated the effects of activin A and inhibin A in modulating the tumor necrosis factor (TNF)-alpha/intercellular adhesion molecule (ICAM)-1 system in cultured human endometrial stromal cells. STUDY DESIGN: Endometrial samples were obtained from 34 reproductive age women undergoing laparoscopy for benign ovarian cysts or infertility. Endometrial stromal cells were cultured and soluble ICAM-1 and TNF-alpha were measured in cell-free supernatants following treatment with or without activin A or inhibin A. Cell surface ICAM-1 was assayed by flow cytometry by staining endometrial cells with specific monoclonal antibodies. RESULTS: Activin A and inhibin A did not influence either the expression of cell surface ICAM-1 or soluble ICAM-1 shedding by cultured endometrial cells. On the other hand, TNF-alpha secretion significantly increased in presence of activin A but not of inhibin A. CONCLUSIONS: Since TNF-alpha modulates several endometrial processes such as menstruation, proliferation, apoptosis, implantation and decidualization, an effect of activin A in the physiological control of endometrium is further supported by the present data.
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Activinas/farmacología , Endometrio/efectos de los fármacos , Factores Inmunológicos/farmacología , Subunidades beta de Inhibinas/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adolescente , Adulto , Células Cultivadas , Endometrio/citología , Femenino , Enfermedades de los Genitales Femeninos/cirugía , Humanos , Inhibinas/farmacología , Molécula 1 de Adhesión Intercelular/biosíntesis , Interleucina-1/farmacología , Laparoscopía , Persona de Mediana Edad , Transducción de Señal/efectos de los fármacos , Células del Estroma/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
PROBLEM: Regeneration and tolerance factor (RTF) has been recently suggested to contribute to the control of fetal-ablating immunity at the maternal-fetal interface through the induction of T helper 2 (Th2)-dominated response. The protein consists of a membrane-associated domain and an extracellular portion which is proteolitically cleaved to yield a soluble peptide. In humans, it has been shown to be expressed by invading cytotrophoblasts and decidual lymphoid cells, to be increased on peripheral blood B lymphocytes during a normal gestation and on circulating natural killer cells during unsuccessful pregnancies. However, the expression of RTF in other cell types and, specifically, in non-hematopoietic maternal cells of the human uterus has not been characterized in detail. Thus, we have specifically studied the expression and modulation of the cytokine in human endometrium obtained in different phases of the cycle and in early pregnancy. METHODS: The 20 kDa extracellular domain of RTF has been localized by immunohistochemical method and Western blot analysis. Levels of RTF messenger RNA (mRNA) in basal and stimulated conditions have been evaluated by semiquantitative reverse transcription-polymerase chain reaction. RESULTS: The extracellular domain of RTF could be detected in both the glandular epithelium and stroma with diffuse distribution in both cycling endometrium and first trimester decidua. Both cycling and pregnant endometrium expressed the gene for RTF but mRNA levels resulted significantly increased in secretory phase-endometrial stromal cells when compared to proliferative phase samples. Inflammatory cytokines, interleukin-1beta and tumour necrosis factor alpha were able to directly increase endometrial RTF mRNA expression. CONCLUSION: These results indicate that RTF is constitutively expressed at endometrial and decidual level and its up-regulation during the secretory phase of the cycle may be relevant in mediating some immune-related aspects of uterine physiology.
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Endometrio/citología , Endometrio/metabolismo , Regulación de la Expresión Génica , Placenta/citología , Placenta/metabolismo , Factores Supresores Inmunológicos/genética , Factores Supresores Inmunológicos/metabolismo , Ciclo Celular , Células Cultivadas , Femenino , Humanos , Inmunohistoquímica , Embarazo , Primer Trimestre del Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
Endometriosis is an estrogen-dependent disorder mostly occurring in reproductive-age women. Various therapies have been used in an attempt to treat endometriosis, including ovarian suppression therapy, surgical treatment or a combination of these strategies. However, in general, substantial surgery remains the primary treatment option for endometriosis at all stages. Recently, aromatase inhibitors and anti-estrogens have been proposed as novel potential candidates. The rationale for the use of aromatase inhibitors is mostly related to the high aromatase expression in endometriotic cysts and extra-ovarian endometriotic implants. Among anti-estrogens, raloxifene has been investigated in animal models with good results, but in premenopausal women, the compound does not seem to suppress estrogen production.
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Inhibidores de la Aromatasa , Endometriosis/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Antagonistas de Estrógenos/uso terapéutico , Femenino , HumanosRESUMEN
Previous reports suggest that systemic and/or placental presence of T helper 2-type cytokines would be supportive of normal pregnancy. Among these cytokines, IL-10 is thought to be produced at the feto-maternal interface to control fetal-ablating immune responses. However, expression of IL-10 in nonhemopoietic maternal cells of the human uterus has not been characterized in detail. Thus, we studied the expression and modulation of the cytokine and its receptor in human endometrial cells obtained in different phases of the cycle and in early pregnancy. Both cycling and pregnant endometrium express the genes for IL-10 and its receptor, but secretion of the cytokine was significantly increased in decidual cultures compared with that by endometrial cells in both proliferative and secretory phases of the cycle. Similarly, the expression of IL-10 receptor mRNA was up-regulated in early decidua compared with that in menstrual cycle-dependent endometrium. IL-1beta, but not gonadal steroid hormones, was able to directly increase endometrial/decidual IL-10 production. Based on the activity of IL-10 in other nonhemopoietic cell populations, we also evaluated its potential effects on TNFalpha secretion and proliferation of endometrial/decidual cells, but we were unable to demonstrate any direct role of IL-10 as a regulator of these specific functions. It is evident that IL-10 and its receptor are normal constituents of endometrium and early decidua, and their up-regulation during early pregnancy may participate in the T helper type 2 predominance at the feto-maternal interface. The inability of the cytokine to exert autocrine effects on TNFalpha secretion and proliferation of decidual cells leads to speculation that the cytokine acts mostly as a paracrine mediator able to affect maternal immune responses.