RESUMO
The current management of psoriasis and its associated resource use in the United Kingdom (UK) was investigated in this retrospective analysis of 789,300 primary care patient records. Most patients with psoriasis (94%) were managed on topical psoriasis agents only, 4% were prescribed systemic psoriasis agents and 2% had no recorded psoriasis treatment at all during the 12-month study period. Co-medications to treat physical or psychological comorbidities were required by 22% of patients. Referral rates into secondary care were low, 5% of patients prescribed systemic psoriasis agents and 0.7% of patients prescribed topical psoriasis agents had secondary care appointments documented in their medical records. This study demonstrates that most patients with psoriasis in UK primary care are managed on topical agents even though there are surrogate markers, such as resource use and co-medication prescriptions, which indicate that their psoriasis is not optimally controlled.
Assuntos
Fármacos Dermatológicos/administração & dosagem , Atenção Primária à Saúde/estatística & dados numéricos , Psoríase/tratamento farmacológico , Administração Cutânea , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimedicação , Padrões de Prática Médica/estatística & dados numéricos , Estudos Retrospectivos , Reino UnidoRESUMO
Human immunodeficiency virus-1 (HIV-1) infection is associated with numerous effects on the nervous system, including pain and peripheral neuropathies. We now demonstrate that cultured rat dorsal root ganglion (DRG) neurons express a wide variety of chemokine receptors, including those that are thought to act as receptors for the HIV-1 coat protein glycoprotein120 (gp120). Chemokines that activate all of the known chemokine receptors increased [Ca(2+)](i) in subsets of cultured DRG cells. Many neurons responded to multiple chemokines and also to bradykinin, ATP, and capsaicin. Immunohistochemical studies demonstrated the expression of the CXCR4 and CCR4 chemokine receptors on populations of DRG neurons that also expressed substance P and the VR1 vanilloid receptor. RT-PCR analysis confirmed the expression of CXCR4, CX3CR1, CCR4, and CCR5 mRNAs in DRG neurons. Chemokines and gp120 produced excitatory effects on DRG neurons and also stimulated the release of substance P. Chemokines and gp120 also produced allodynia after injection into the rat paw. Thus these results provide evidence that chemokines and gp120 may produce painful effects via direct actions on chemokine receptors expressed by nociceptive neurons. Chemokine receptor antagonists may be important therapeutic interventions in the pain that is associated with HIV-1 infection and inflammation.
Assuntos
Quimiocinas/metabolismo , Proteína gp120 do Envelope de HIV/farmacologia , Hiperalgesia/fisiopatologia , Neurônios/metabolismo , Nociceptores/metabolismo , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Bradicinina/farmacologia , Cálcio/metabolismo , Capsaicina/farmacologia , Células Cultivadas , Quimiocinas/farmacologia , Corantes Fluorescentes , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Inflamação/metabolismo , Líquido Intracelular/metabolismo , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Nociceptores/citologia , Nociceptores/efeitos dos fármacos , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Receptores CCR4 , Receptores CXCR4/biossíntese , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Substância P/metabolismoRESUMO
It has been hypothesized that R-type Ca currents result from the expression of the alpha(1E) gene. To test this hypothesis we examined the properties of voltage-dependent Ca channels in mice in which the alpha(1E) Ca channel subunit had been deleted. Application of omega-conotoxin GVIA, omega-agatoxin IVA, and nimodipine to cultured cerebellar granule neurons from wild-type mice inhibited components of the whole-cell Ba current, leaving a "residual" R current with an amplitude of approximately 30% of the total Ba current. A minor portion of this R current was inhibited by the alpha(1E)-selective toxin SNX-482, indicating that it resulted from the expression of alpha(1E). However, the majority of the R current was not inhibited by SNX-482. The SNX-482-sensitive portion of the granule cell R current was absent from alpha(1E) knock-out mice. We also identified a subpopulation of dorsal root ganglion (DRG) neurons from wild-type mice that expressed an SNX-482-sensitive component of the R current. However as with granule cells, most of the DRG R current was not blocked by SNX-482. We conclude that there exists a component of the R current that results from the expression of the alpha(1E) Ca channel subunit but that the majority of R currents must result from the expression of other Ca channel alpha subunits.
Assuntos
Canais de Cálcio Tipo R/genética , Canais de Cálcio Tipo R/metabolismo , Animais , Bário/farmacologia , Western Blotting , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo R/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Eletrofisiologia , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Transporte de Íons/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nimodipina/farmacologia , Técnicas de Patch-Clamp , Subunidades Proteicas , Venenos de Aranha/farmacologia , Transmissão Sináptica/efeitos dos fármacos , ômega-Agatoxina IVA/farmacologia , ômega-Conotoxina GVIA/farmacologiaRESUMO
We examined the ability of different G protein subunits to inhibit the activity of human alpha1B and alpha1E Ca2+ channels stably expressed in human embryonic kidney (HEK) 293 cells together with beta1B and alpha2Bdelta Ca2+ channel subunits. Under normal conditions, Ca2+ currents in alpha1B-expressing cells showed little facilitation after a depolarizing prepulse. However, when we overexpressed the beta2gamma2 subunits of heterotrimeric G proteins, the time course of activation of the Ca2+ currents was considerably slowed and a depolarizing prepulse produced a large facilitation of the current as well as an acceleration in its time course of activation. Similar effects were not observed when cells were transfected with constitutively active mutants of the G protein alpha subunits alpha s, alpha i1, and alpha o or with the G protein beta2 and gamma2 subunits alone. Studies carried out in cells expressing alpha1E currents showed that overexpression of beta2gamma2 subunits produced pre-pulse facilitation, although this was of lesser magnitude than that observed with Ca2+ currents in alpha1B-expressing cells. The subunits beta2 and gamma2 alone produced no effects, nor did constitutively active alpha s, alpha i1, and alpha o subunits. Phorbol esters enhanced alpha1E Ca2+ currents but had no effect on alpha1B currents, suggesting that protein kinase C activation was not responsible for the observed effects. When alpha1E Ca2+ currents were expressed without their beta subunits, they exhibited prepulse facilitation. These results demonstrate that alpha1E Ca2+ currents are less susceptible to direct modulation by G proteins than alpha1B currents and illustrate the antagonistic interactions between Ca2+ channel beta subunits and G proteins.
Assuntos
Canais de Cálcio/fisiologia , Proteínas de Ligação ao GTP/fisiologia , Neurônios/fisiologia , Linhagem Celular , Humanos , Ativação do Canal Iônico , Técnicas de Patch-Clamp , Proteínas Recombinantes , Relação Estrutura-Atividade , TransfecçãoRESUMO
Neuronal voltage-dependent calcium channels (VDCCs) each comprising of alpha 1, alpha 2 delta, and beta subunits, are one mechanism by which excitable cells regulate the flux of calcium ions across the cell membrane following depolarisation Studies have shown the expression of several alpha 1 and beta subtypes within neuronal tissue. The comparative distribution of these in normal human brain is largely unknown. The aim of this work is to prepare antibodies directed specifically to selected subunits of human neuronal VDCCs for use in biochemical and mapping studies of calcium channel subtypes in the brain. Previous studies have defined DNA sequences specific for each subunit Comparison of these sequences allows the selection of unique amino acid sequences for use as immunogens which are prepared as glutathione-S-transferase (GST) fusion proteins in E. coli. Polyclonal antibodies raised against these fusion proteins are purified by Protein A chromatography, followed by immunoaffinity chromatography and extensive adsorptions using the appropriate fusion protein-GST Sepharose 4B columns. The resultant antibodies are analysed for specificity against the fusion proteins by ELISA, and by immunofluorescence and Western immunoblot analysis of recombinant HEK293 cells stably transfected with cDNAs encoding alpha 1, alpha 2 delta and beta subunits.
Assuntos
Anticorpos/imunologia , Anticorpos/isolamento & purificação , Canais de Cálcio/imunologia , Canais de Cálcio/fisiologia , Neurônios/metabolismo , Animais , Especificidade de Anticorpos , Antígenos/imunologia , Western Blotting , Linhagem Celular , Eletrofisiologia , Ensaio de Imunoadsorção Enzimática , Escherichia coli/metabolismo , Imunofluorescência , Humanos , Imunização , Coelhos , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Treatment of cerebellar neurones in culture with an antisense oligonucleotide (ODN) against alpha1A, reduced the whole-cell P-type calcium channel current relative to mismatch ODN treated controls (p < 0.001). Therefore, AgaIVA (50 nM) reduced whole-cell calcium current in mismatch and antisense treated cells by 70 +/- 4 and 19 +/- 3%, respectively.