RESUMO
In this cross-sectional study we examined whether the prevalence of treatment resistant depression (TRD) can be partly attributed to level of bipolarity. We included data of 201 patients with either episodic depression or TRD, who received treatment for their depression at either an outpatient or 2nd opinion/daytime setting, within a specialised mental healthcare department in the Netherlands. Whether level of TRD, assessed by the 'Dutch Measure for quantification of Treatment Resistance in Depression', can be partly explained by level of bipolarity, assessed by 'the Bipolarity Index', was examined using linear regression. We found no direct association between level of TRD and level of bipolarity, nor did comorbid anxiety disorders obscure an existing association. In this study we found no evidence for overlooked bipolarity contributing to the high prevalence of TRD. If replicated, we could state that additional screening on bipolarity with an instrument such as the 'Bipolarity Index' in the specialised mental health care is unnecessary.
Assuntos
Depressão , Transtorno Depressivo Resistente a Tratamento , Transtornos de Ansiedade/epidemiologia , Estudos Transversais , Transtorno Depressivo Resistente a Tratamento/diagnóstico , Transtorno Depressivo Resistente a Tratamento/epidemiologia , Transtorno Depressivo Resistente a Tratamento/terapia , Humanos , PrevalênciaAssuntos
Dermatite Atópica/microbiologia , Lipídeos/química , Infecções Cutâneas Estafilocócicas/metabolismo , Staphylococcus aureus , Adulto , Idoso , Dermatite Atópica/metabolismo , Regulação para Baixo/fisiologia , Epiderme/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Retinoids play critical regulatory roles in the maintenance of mammalian epithelia and exert pleiotropic effects through nuclear receptors. RXRalpha, which is a ligand-dependent transcription factor, is the most abundant RXR isotype expressed in cervical epithelia, and may play a crucial role in cervix development and homeostasis. We have previously described a mouse model to induce the temporally controlled epithelia-specific somatic mutagenesis of RXRalpha alleles in epidermis. To study the role of RXRalpha in cervical homeostasis, we ablated RXRalpha in cervix epithelial cells of adult mice. We found that such mutant mice develop ectocervical atrophy with moderate epidermoid metaplasia. In addition, we report a simultaneous increase of cell proliferation and apoptosis levels accompanied by alteration in the expression of genes involved in both processes.
Assuntos
Colo do Útero/fisiologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/fisiologia , Animais , Apoptose , Proliferação de Células , Epiderme/metabolismo , Feminino , Homeostase , Ligantes , Camundongos , Camundongos Mutantes , Mutagênese , MutaçãoRESUMO
Nuclear receptors for retinoids (RARs) and vitamin D (VDR), and for some other ligands (TRs, PPARs and LXRs), maybe critical in the development and homeostasis of mammalian epidermis. It is believed that these receptors form heterodimers with retinoid X receptors (RXRs) to act as transcriptional regulators. However, most genetic approaches aimed at establishing their physiological functions in the skin have been inconclusive owing either to pleiotropic effects and redundancies between receptor isotypes in gene knockouts, or to equivocal interpretation of dominant-negative mutant studies in transgenic mice. Moreover, knockout of RXRalpha, the main skin RXR isotype, is lethal in utero before skin formation. Here we have resolved these problems by developing an efficient technique to create spatiotemporally controlled somatic mutations in the mouse. We used tamoxifen-inducible Cre-ER(T) recombinases to ablate RXRalpha selectively in adult mouse keratinocytes. We show that RXRalpha has key roles in hair cycling, probably through RXR/VDR heterodimers, and in epidermal keratinocyte proliferation and differentiation.
Assuntos
Receptores do Ácido Retinoico/fisiologia , Dermatopatias/etiologia , Fenômenos Fisiológicos da Pele , Fatores de Transcrição/fisiologia , Proteínas Virais , Alelos , Alopecia/etiologia , Alopecia/genética , Alopecia/patologia , Animais , Feminino , Cabelo/fisiologia , Humanos , Integrases/biossíntese , Queratinócitos/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Mutagênese , Receptores do Ácido Retinoico/genética , Receptores X de Retinoides , Dermatopatias/genética , Dermatopatias/patologia , Tamoxifeno , Fatores de Transcrição/genéticaRESUMO
Gene targeting in the mouse is a powerful tool to study mammalian gene function. The possibility to efficiently introduce somatic mutations in a given gene, at a chosen time and/or in a given cell type will further improve such studies, and will facilitate the generation of animal models for human diseases. To create targeted somatic mutations in the epidermis, we established transgenic mice expressing the bacteriophage P1 Cre recombinase or the tamoxifen-dependent Cre-ER(T2) recombinase under the control of the human keratin 14 (K14) promoter. We show that LoxP flanked (floxed) DNA segments were efficiently excised in epidermal keratinocytes of K14-Cre transgenic mice. Furthermore, Tamoxifen administration to adult K14-Cre-ER(T2) mice efficiently induced recombination in the basal keratinocytes, whereas no background recombination was detected in the absence of ligand treatment. These two transgenic lines should be very useful to analyse the functional role of a number of genes expressed in keratinocytes.
Assuntos
Epiderme/fisiologia , Marcação de Genes , Mutagênese Sítio-Dirigida , Animais , Bacteriófago P1/enzimologia , Células Epidérmicas , Epiderme/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Humanos , Integrases/genética , Queratina-14 , Queratinócitos/efeitos dos fármacos , Queratinócitos/fisiologia , Queratinas/genética , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Receptores de Estrogênio/genética , Recombinação Genética , Tamoxifeno/farmacologia , Proteínas Virais/genéticaRESUMO
Conditional DNA excision between two LoxP sites can be achieved in the mouse using Cre-ER(T), a fusion protein between a mutated ligand binding domain of the human estrogen receptor (ER) and the Cre recombinase, the activity of which can be induced by 4-hydroxy-tamoxifen (OHT), but not natural ER ligands. We have recently characterized a new ligand-dependent recombinase, Cre-ER(T2), which was approximately 4-fold more efficiently induced by OHT than Cre-ER(T) in cultured cells. In order to compare the in vivo efficiency of these two ligand-inducible recombinases to generate temporally-controlled somatic mutations, we have engineered transgenic mice expressing a LoxP-flanked (floxed) transgene reporter and either Cre-ER(T) or Cre-ER(T2) under the control of the bovine keratin 5 promoter that is specifically active in the epidermis basal cell layer. No background recombinase activity could be detected, while recombination was induced in basal keratinocytes upon OHT administration. Interestingly, a dose-response study showed that Cre-ER(T2) was approximately 10-fold more sensitive to OHT induction than Cre-ER(T).