RESUMO
BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T. METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity. RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype. CONCLUSION: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.
Assuntos
Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Mutação , Neoplasias/enzimologia , Neoplasias/prevenção & controle , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Ataxia Telangiectasia/enzimologia , Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/prevenção & controle , Neoplasias da Mama/enzimologia , Neoplasias da Mama/prevenção & controle , Criança , Feminino , Humanos , Immunoblotting , Estimativa de Kaplan-Meier , Linfoma/enzimologia , Linfoma/prevenção & controle , Masculino , Países Baixos , Proteínas Serina-Treonina Quinases/genética , Reino Unido , Adulto JovemRESUMO
Successful vaccines against serogroup A and C meningococcal strains have been developed, but current serogroup B vaccines provide protection against only a limited range of strains. The ideal meningococcal vaccine would provide cross-reactive immunity against the variety of strains that may be encountered in any community, but it is unclear whether the meningococcus possesses immune targets that have the necessary level of cross-reactivity. We have generated a phoP mutant of the meningococcus by allele exchange. PhoP is a component of a two-component regulatory system which in other bacteria is an important regulator of virulence gene expression. Inactivation of the PhoP-PhoQ system in Salmonella leads to avirulence, and phoP mutants have been shown to confer protection against virulent challenge. These mutants have been examined as potential live attenuated vaccines. We here show that a phoP mutant of the meningococcus is avirulent in a mouse model of infection. Moreover, infection of mice with the phoP mutant stimulated a bactericidal immune response that not only killed the infecting strain but also showed cross-reactive bactericidal activity against a range of strains with different serogroup, serotype, and serosubtyping antigens. Sera from the mutant-infected mice contained immunoglobulin G that bound to the surface of a range of meningococcal strains and mediated opsonophagocytosis of meningococci by human phagocytic cells. The meningococcal phoP mutant is thus a candidate live, attenuated vaccine strain and may also be used to identify cross-reactive protective antigens in the meningococcus.
Assuntos
Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/genética , Infecções Meningocócicas/imunologia , Neisseria meningitidis/imunologia , Neisseria meningitidis/patogenicidade , Animais , Anticorpos Antibacterianos/sangue , Atividade Bactericida do Sangue , Linhagem Celular , Reações Cruzadas , Regulação Bacteriana da Expressão Gênica , Humanos , Infecções Meningocócicas/microbiologia , Camundongos , Mutação , Neisseria meningitidis/classificação , Neisseria meningitidis/genética , Proteínas Opsonizantes , Fagocitose , Polimixina B/farmacologia , VirulênciaAssuntos
Depressão/metabolismo , Dor/metabolismo , Transtornos Fóbicos/metabolismo , Hormônio Adrenocorticotrópico/fisiologia , Idoso , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Etanol/farmacologia , Feminino , Glucocorticoides/metabolismo , Glutamatos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/metabolismo , Dor/tratamento farmacológico , Transtornos Fóbicos/tratamento farmacológico , Serotonina/metabolismo , Triptofano/metabolismoRESUMO
The use of clomipramine in a large suburban general practice is reviewed. Three hundred and fifty patients have been treated to date out of a total practice population of twenty-one thousand. It is argued that phobic anxiety states are much commoner than is normally supposed and that they are usually associated with a history of separation or rejection in childhood. A combined treatment regime is employed for one month thereafter clomipramine alone is used. Side-effects may initially present a problem although they may not all be truly drug induced. Some patients use side-effects to manipulate the clinical situation. However proper interpretative management of side effects can assist the clinicians in persuading patients to continue therapy. Some impressive results have been obtained with clomipramine therapy. Illustrative case histories are provided.