RESUMO
BACKGROUND: Eczema and asthma are chronic diseases with onset usually before the age of 5 years. More than 50% of individuals with eczema will develop asthma and/or other allergic diseases. Several loss-of-function mutations in filaggrin (FLG) have been identified in patients with eczema. However, the association of FLG with healthcare use is unknown. OBJECTIVES: To determine whether FLG mutations are associated with increased prescribing for eczema and asthma and whether increased prescribing is associated with increased healthcare costs. METHODS: A secondary analysis of BREATHE, a cross-sectional study of gene-environment associations with asthma severity, was undertaken. BREATHE data was collected for 1100 participants with asthma, in Tayside and Fife, Scotland during the period 2003-2005. Through collaboration with the Health Informatics Centre in Dundee, BREATHE was linked to accident and emergency, community prescribing and Scottish morbidity records. The data linkage allowed longitudinal exploration of associations between genetic variation and prescribing. RESULTS: An association was found between FLG mutations and increased prescribing for mild and moderate eczema, asthma-reliever medicine and asthma exacerbations. A strong association was found between FLG mutations and prescribing of emollients [incidence rate ratio (IRR) 2·19, 95% confidence interval (CI) 1·36-3·52], treatment for severe eczema (IRR 2·18, 95% CI 1·22-3·91) and a combination of a long-acting ß2 -agonist and corticosteroids (IRR 3·29, 95% CI 1·68-6·43). CONCLUSIONS: The presence of FLG mutations in this cohort is associated with increased prescribing for eczema and asthma. Randomized controlled trials are required to determine if these individuals could benefit from management strategies to reduce morbidity and treatment costs.
Assuntos
Asma/terapia , Doença Crônica/terapia , Eczema/terapia , Custos de Cuidados de Saúde/estatística & dados numéricos , Proteínas de Filamentos Intermediários/genética , Proteínas S100/genética , Adolescente , Adulto , Antiasmáticos/economia , Antiasmáticos/uso terapêutico , Asma/economia , Asma/genética , Criança , Pré-Escolar , Doença Crônica/economia , Estudos Transversais , Análise Mutacional de DNA , Prescrições de Medicamentos/estatística & dados numéricos , Eczema/economia , Eczema/genética , Emolientes/economia , Emolientes/uso terapêutico , Feminino , Proteínas Filagrinas , Predisposição Genética para Doença , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Mutação com Perda de Função , Masculino , Medicamentos sob Prescrição/economia , Medicamentos sob Prescrição/uso terapêutico , Escócia , Fatores de Tempo , Adulto JovemRESUMO
The covalent attachment of poly(ethylene glycol) (PEG) to therapeutic proteins is a commonly used approach for extending in vivo half-lives. A potential limitation of this PEGylation strategy is the adverse effect of PEG on conjugate viscosity. Interferon-alpha (IFN) was conjugated via its N-terminal amino group by reductive amination to α-aldehyde functional comb-shaped PolyPEG polymers (50 and 70 kDa) and to linear PEG (30 kDa). In vitro potencies of the purified PEGylated IFN conjugates were measured by reporter gene assay using a HEK293P/ISRE-SEAP cell line. IFN levels were measured in rats following intravenous injection. Viscosities of various linear PEG and PolyPEG polymers along with the polymer-IFN conjugates were determined using a rotational rheometer with cone-and-plate geometry. In vitro potencies and half-lives of the PEGylated IFN conjugates were compared with those of the marketed branched PEG-IFN conjugate PEGASYS. Both PolyPEG-IFN conjugates retained a similar potency as that of the marketed comparator, whereas the linear PEG-IFN conjugate potency was greater. All conjugates showed extended half-lives compared to that of naked IFN, with the PolyPEG conjugates exhibiting the longest half-lives and the linear PEG conjugate, the shortest. Viscosity analysis showed that the linear PEG-IFN conjugate was over twice as viscous as both PolyPEG conjugates. Taken together, this work demonstrates the potential of PolyPEG conjugation to therapeutic proteins as a novel tool for optimizing pharmacokinetic profiles in a way that potentially allows administration of high-dose formulations because of lower conjugate viscosity.
Assuntos
Interferon-alfa/sangue , Interferon-alfa/química , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Animais , Feminino , Células HEK293 , Meia-Vida , Humanos , Ratos , Ratos Wistar , ViscosidadeRESUMO
Hereditary angioedema (HAE) is a rare disease characterized by episodes of potentially life-threatening angioedema. For affected children in the United Kingdom, there are relatively few data regarding disease prevalence, service organization and the humanistic burden of the disease. To improve knowledge in these areas, we surveyed major providers of care for children with HAE. A questionnaire was sent to major paediatric centres to determine patient numbers, symptoms, diagnostic difficulties, management and available services. In addition, all patients at a single centre were given a questionnaire to determine the experiences of children and their families. Sixteen of 28 centres responded, caring for a total of 111 UK children. Seven children had experienced life-threatening crises. One-third of patients were on long-term prophylactic medication, including C1 inhibitor prophylaxis in four children. Eight centres reported patients who were initially misdiagnosed. Broad differences in management were noted, particularly regarding indications for long-term prophylaxis and treatment monitoring. We also noted substantial variation in the organization of services between centres, including the number of consultants contributing to patient care, the availability of specialist nurses, the availability of home therapy training and the provision of patient information. Ten of 12 patient/carer questionnaires were returned, identifying three common themes: the need to access specialist knowledge, the importance of home therapy and concerns around the direct effect of angioedema on their life. To our knowledge, this study represents the first dedicated survey of paediatric HAE services in the United Kingdom and provides useful information to inform the optimization of services.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Serviços de Saúde , Humanos , Masculino , Inquéritos e Questionários , Reino UnidoRESUMO
BACKGROUND: Mannose-binding lectin (MBL) deficiency has been associated with infections of the respiratory tract and with increased disease severity in cystic fibrosis (CF). The mechanism is uncertain, and could relate either to systemic or local effects. The aim of this study was to determine, in a large cohort of children, whether MBL is present on the airway surface in health or disease. METHODS: Bronchoalveolar lavage (BAL) fluid from children with and without respiratory infection (some with underlying disease) was analysed for MBL and neutrophil elastase (NE). Levels were compared between groups, and correlations were examined with local and systemic inflammatory markers, infective organisms and load. RESULTS: 85 children were recruited to the study. MBL was absent in the lavage of all 7 children without lung infection but present in 62% (8/13) of those with acute pneumonia/pneumonitis, 23% (5/22) with recurrent respiratory tract infections, 17% (1/6) with primary ciliary dyskinesia and 8% (3/37) with CF (p<0.01). Children with acute pneumonia/pneumonitis had significantly higher levels than those in the other groups. There was no relationship with organisms cultured or systemic markers of inflammation, although in the group with detectable MBL in the BAL fluid, the levels correlated positively with levels of NE. CONCLUSIONS: MBL is undetectable in the non-infected airway but is present in a significant number of samples from children with lung infection. The levels found in the BAL fluid could be physiologically active and the protein may therefore be playing a role in host defence.
Assuntos
Brônquios/química , Broncopatias/metabolismo , Líquido da Lavagem Broncoalveolar/química , Lectina de Ligação a Manose/metabolismo , Infecções Respiratórias/metabolismo , Adolescente , Bactérias/isolamento & purificação , Broncopatias/microbiologia , Líquido da Lavagem Broncoalveolar/microbiologia , Criança , Pré-Escolar , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Haplótipos , Humanos , Lactente , Elastase de Leucócito/metabolismo , Masculino , Inibidores de Proteases/farmacologia , Recidiva , Infecções Respiratórias/microbiologia , Vírus/isolamento & purificaçãoRESUMO
BACKGROUND: The systemic inflammatory response syndrome (SIRS) may be triggered by endotoxin. Humans have antibodies directed against the core of endotoxin (endotoxin core antibodies, EndoCAb) that appear to be protective following surgery and in sepsis. We hypothesised that children with elevated antibodies to endotoxin core would be less likely to develop SIRS in their initial period on intensive care. Because of the existing literature we defined two sub-groups according to the primary reason for ICU admission: infection and non-infection. METHODS: We recruited 139 consecutive patients admitted to a paediatric intensive care unit (PICU) with more than one organ failure for longer than 12 h as part of another study. Patients were classified on admission to PICU as having an infectious or a non-infections diagnosis. The occurrence of SIRS within 48 h of admission was recorded along with detailed clinical and demographic data, EndoCAb concentration and the potential confounding variables C-reactive protein and mannose-binding lectin. RESULTS: In the 71 patients admitted without infection (primarily post-operative and head injured) IgG EndoCAb was significantly lower in patients who developed SIRS than those who did not (72 vs. 131 MU/ml), independent of potential confounding variables. In patients with infection there was no significant difference in IgG EndoCAb between children developing SIRS and those who did not (111 vs. 80 MU/ml). CONCLUSION: Head injured and post-operative patients admitted to PICU who develop early SIRS have significantly lower serum IgG EndoCAb levels than those who do not.
Assuntos
Estado Terminal , Endotoxemia/complicações , Endotoxemia/imunologia , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fatores de Risco , Estatísticas não Paramétricas , Síndrome de Resposta Inflamatória Sistêmica/sangueRESUMO
Expansion of a polymorphic GCC-repeat at the FRAXE locus has been associated with expression of chromosome fragility at this site and cognitive impairment in some individuals previously testing negative for CGG-repeat expansion in the fragile X mental retardation-1 (FMR1) gene. To determine the frequency of FRAXE triplet repeat expansion among persons with developmental disability, 396 individuals from two institutions were studied, all of whom were negative for FMR1 repeat expansion. Clinically, there was a wide range of mental impairment, with the majority (61.1%) being severely to profoundly affected. The distribution of FRAXE GCC-repeat numbers in the study population was 5-38: 28 (5.6%) with 10-14 repeats; 366 (73.8%) with 15-19 repeats; 74 (14.9%) with 20-24 repeats; 20 (4.0%) with 25-29 repeats; and 5 (1.0%) with 30-38 repeats, with no individuals demonstrating repeat expansion. One profoundly retarded male was found to have a deletion of about 40 bp. Southern blots of HindIII-digested DNAs from individuals with > or = 26 repeats all showed normal patterns. These results suggest that FRAXE GCC-repeat expansion is not a common cause of developmental disability in institutionalized persons with mild to profound mental retardation.
Assuntos
Fragilidade Cromossômica , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Repetições de Trinucleotídeos , Cromossomo X , Adulto , Criança , Deficiências do Desenvolvimento/classificação , Feminino , Humanos , Pacientes Internados , Deficiência Intelectual/classificação , Masculino , Reação em Cadeia da Polimerase , Polimorfismo GenéticoRESUMO
Infant feeding practices are influenced by many factors including culture, household income, literacy, advice from health care workers and advertising. In South India doctors play a very significant role in influencing a mother's decision about when or whether to supplement breastfeeding with formula feeds. Doctors exert their influence on mothers both directly and indirectly, and they are increasingly targeted by commercial infant food companies. Doctors need continuing education about nutrition education, lactation management, and a greater awareness about the influence of inappropriate promotional practices by companies.
PIP: Infant feeding practices are influenced by many factors, including culture, household income, literacy, advice from health care workers, and advertising. Doctors in South India play a major role in influencing a mother's decision about when or whether to supplement breastfeeding with formula feeds. For example, 152 mothers were interviewed after attending mother and child health outpatient clinics at two hospitals in Mangalore, Karnataka, South India. 45% of the interviews were conducted at a private hospital and the remainder at a government hospital. Only mothers with children under age 7 years were accepted to participate. They reported doctors as being the largest single group source of information concerning formula feed, followed by relatives and advertising. Mothers were more likely to receive advice from a doctor about feeding if they were literate, not low caste, living in an urban or semi-rural setting, or receiving a relatively higher weekly income. Doctors exert their influence upon mothers both directly and indirectly, and they are increasingly targeted by commercial infant food companies. They require continuing education about nutrition education, lactation management, and a greater awareness about the influence of inappropriate promotional practices by companies.
Assuntos
Promoção da Saúde , Fenômenos Fisiológicos da Nutrição do Lactente , Papel do Médico , Aleitamento Materno , Pré-Escolar , Feminino , Humanos , Índia , Lactente , Alimentos Infantis , MãesAssuntos
Arritmias Cardíacas/tratamento farmacológico , Indóis/uso terapêutico , Amidas/uso terapêutico , Anestésicos Locais/farmacologia , Animais , Arritmia Sinusal/tratamento farmacológico , Arritmias Cardíacas/induzido quimicamente , Pressão Sanguínea/efeitos dos fármacos , Gatos , Epinefrina , Feminino , Cobaias , Halotano , Íleo/efeitos dos fármacos , Técnicas In Vitro , Lidocaína/farmacologia , Lidocaína/uso terapêutico , Masculino , Contração Muscular/efeitos dos fármacos , Nicotina/farmacologia , Ouabaína , Piperidinas/uso terapêutico , Procaína/farmacologia , Propranolol/uso terapêutico , Quinidina/farmacologia , Taquicardia/tratamento farmacológico , Fibrilação Ventricular/tratamento farmacológicoAssuntos
Infecções Urinárias/diagnóstico , Algoritmos , Antibacterianos/uso terapêutico , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/etiologia , Criança , Pré-Escolar , Medicina de Família e Comunidade , Humanos , Masculino , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/etiologiaRESUMO
The speed of onset and intubation conditions have been compared for suxamethonium 1 mg/kg, alcuronium 0-32 mg/kg and fazadinium 1 mg/kg and 1-25 mg/kg. Fazadinium 1 mg/kg was not significantly different in times to intubation from suxamethonium although the latter gave a highly significant greater number of patients with excellent conditions. The higher dose of 1-25 mg/kg fazadinium did not give significantly better intubating conditions than the lower dose. Although the times to intubation for the two dose levels of fazadinium did not differ statistically, the higher dose was significantly slower in onset than suxamethonium. Alcuronium was slower than either suxamethonium or fazadinium 1 mg/kg in producing satisfactory conditions. The nondepolarizing drug, fazadinium, may be a useful neuromuscular blocking agent in emergency cases where rapid intubation is required and when it is wished to avoid possible or probable adverse effects from the depolarising drug suxamethonium.
Assuntos
Intubação Intratraqueal , Compostos de Piridínio , Adolescente , Adulto , Idoso , Alcurônio , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Succinilcolina , Fatores de TempoRESUMO
Fazadinium at two dose levels (1 mg/kg and 1.5 mg/kg) and suxamethonium at three dose levels (50 mg, 75 mg and 100 mg) were investigated in 106 adult patients to determine the time interval from injection to tracheal intubation. The intubating conditions were graded according to the scheme described by Lund and Stovner. Suxamethonium 100 mg gave the shortest time interval between the end of injection and intubation. There was no significant difference between the intubation time when smaller doses of suxamethonium (50 mg and 75 mg were used and those when AH8165 (1 mg and 1.5 mg/kg) were given. Suxamethonium 100 mg also produced a significantly higher incidence of excellent intubating conditions. The clinical implications of the findings are discussed.
Assuntos
Intubação Intratraqueal , Relaxantes Musculares Centrais/administração & dosagem , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Succinilcolina/administração & dosagem , Adulto , Idoso , Ensaios Clínicos como Assunto , Feminino , Humanos , Intubação Intratraqueal/efeitos adversos , Masculino , Pessoa de Meia-Idade , Compostos de Piridínio/administração & dosagem , Compostos de Piridínio/farmacologia , Succinilcolina/farmacologiaRESUMO
The clinical use of the neuromuscular blocking agent fazadinium was investigated in a survey of 500 patients. Rapid conditions for tracheal intubation followed by excellent relaxation and easy antagonism were obtained. It is suggested that these findings commend it as an alternative to suxamethonium. Tachycardia appeared to be the only disadvantage associated with its use.
Assuntos
Bloqueio Nervoso/métodos , Compostos de Piridínio , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Intubação Intratraqueal , Masculino , Pessoa de Meia-Idade , Compostos de Piridínio/administração & dosagem , Compostos de Piridínio/efeitos adversos , Compostos de Piridínio/antagonistas & inibidoresRESUMO
Desmoids are uncommon proliferations of fibroblasts that occur with disproportionate frequency in patients with familial adenomatous polyposis. They do not metastasize and are histologically benign. Despite this, the unpredictable and often aggressive nature of familial adenomatous polyposis-associated desmoids and their tendency to occur in intra-abdominal sites means that they present a difficult management problem, and they are a leading cause of death in patients with familial adenomatous polyposis who have undergone colectomy. We report a case of a patient with familial adenomatous polyposis who had extensive and aggressive desmoid disease and whose management was further complicated by a large intrahepatic desmoid. There are no previous reports of desmoids occurring in the liver.
Assuntos
Polipose Adenomatosa do Colo/complicações , Fibromatose Agressiva/complicações , Neoplasias Hepáticas/complicações , Adolescente , Feminino , Fibromatose Agressiva/diagnóstico por imagem , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
The prevalence of increased anterior atlanto-odontoid distance (AAOD), a risk factor for spinal cord compression, and degenerative disease of the cervical spine (DDCS) in a population of institutionalized adults with Down's syndrome (DS) was determined and compared with age- and sex-matched 'normals' presenting to a hospital emergency department. Radiographs of the cervical spines of 99 adults with DS and 198 'normals' were compared using a standardized rating scale. The prevalence of an AAOD of 3 mm or greater, the threshold of risk from the literature, was 8% for DS cases and 2% for controls (P < 0.01). The mean AAOD for DS cases was 2.0 +/- 1 mm and for controls 1.5 +/- 0.5 mm (P < 0.01). There was a negative correlation between AAOD and age of DS cases. The prevalence of any degree of DDCS among the DS cases was 64%, the controls 39% (P < 0.001); for moderate or severe DDCS the prevalence among DS cases was 45%, controls 12% (P < 0.001). The prevalence of DDCS increased with age in both groups, but the severity of DDCS was significantly increased with age in both groups, but the severity of DDCS was significantly greater for DS individuals in all age groups. The levels of the cervical spine affected ranged from C2 to C6; the most commonly affected level was C5-C6. While DS adults are at increased theoretical risk for spinal cord compression due to increased AAOD, its clinical significance would appear to be small and to decline with age.(ABSTRACT TRUNCATED AT 250 WORDS)