RESUMO
BACKGROUND: The relationship between obesity and health-related quality of life (HRQoL) may be confounded by factors such as multimorbidity. The aim of the study was to explore this relationship, controlling for long-term conditions and other health, lifestyle and demographic factors in a general adult population. There was specific interest in the impact of high weight status, measured by body mass index (BMI) levels (obesity, morbid obesity) compared with individuals of normal weight. METHODS: Health, lifestyle and demographic data were collected from 64,631 individuals aged 16 years and over registered in the Yorkshire Health Study; a long-term cohort study. Data were collected in 2 waves: from patients attending GP surgeries in the South Yorkshire region; and using online recruitment across the entire Yorkshire and Humber area. Univariable and multivariable regression methods were utilised to identify factors associated with HRQoL as measured by the EQ-5D summary score. Long-term conditions were tested as both covariates and mediating factors on the causal pathway between obesity and HRQoL. RESULTS: Increasing levels of obesity are associated with reduced HRQoL, although this difference is negligible between those of normal weight and those who are overweight. Individuals with obesity and morbid obesity score 4.9 and 11.3 percentage points less on the EQ-5D summary scale respectively than those of normal weight. Concurrent physical, and particularly mental health-related long-term conditions are substantively related to HRQoL: those with 3 or more reported mental or physical health conditions score 29.8 and 14.6 percentage points less on the EQ-5D summary scale respectively than those with fewer conditions. Long-term conditions can be conceptualised as lying on the causal path between obesity and HRQoL, but there is weak evidence for a partial mediating relationship only. CONCLUSIONS: To conclude, in agreement with the established literature we have found a clear inverse relationship between increasing weight status and decreasing HRQoL and confirmed the mediating role of long-term conditions in the reduction of HRQoL in people with obesity. Nevertheless, a high BMI remains independently related to HRQoL, suggesting that 'healthy people with obesity' may be in transition to an unhealthy future.
Assuntos
Obesidade , Qualidade de Vida , Adulto , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Humanos , Obesidade/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: In many countries, screening for colorectal cancer (CRC) relies on repeat testing using the guaiac faecal occult blood test (gFOBT). This study aimed to compare gFOBT performance measures between initial and repeat screens. METHODS: Data on screening uptake and outcomes from the English Bowel Cancer Screening Programme (BCSP) for the years 2008 and 2011 were used. An existing CRC natural history model was used to estimate gFOBT sensitivity and specificity, and the cost-effectiveness of different screening strategies. RESULTS: The gFOBT sensitivity for CRC was estimated to decrease from 27.35% at the initial screen to 20.22% at the repeat screen. Decreases were also observed for the positive predictive value (8.4-7.2%) and detection rate for CRC (0.19-0.14%). Assuming equal performance measures for both the initial and repeat screens led to an overestimate of the cost effectiveness of gFOBT screening compared with the other screening modalities. CONCLUSIONS: Performance measures for gFOBT screening were generally lower in the repeat screen compared with the initial screen. Screening for CRC using gFOBT is likely to be cost-effective; however, the use of different screening modalities may result in additional benefits. Future economic evaluations of gFOBT should not assume equal sensitivities between screening rounds.
Assuntos
Adenoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , Guaiaco , Sangue Oculto , Idoso , Colonoscopia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: The aim was to perform an economic evaluation of the cost-effectiveness of endovascular enhancements to percutaneous transluminal balloon angioplasty (PTA) with bail-out bare metal stents for infrainguinal peripheral arterial disease. METHODS: The following interventions were considered: PTA with no bail-out stenting, PTA with bail-out drug-eluting stents, drug-coated balloons, primary bare metal stents, primary drug-eluting stents, endovascular brachytherapy, stent-grafts and cryoplasty. A discrete-event simulation model was developed to assess the relative cost-effectiveness of the interventions from a health service perspective over a lifetime. Populations of patients with intermittent claudication (IC) and critical leg ischaemia (CLI) were modelled separately. Univariable and probabilistic sensitivity analyses were undertaken. Effectiveness was measured by quality-adjusted life-years (QALYs). RESULTS: For both patient populations, the use of drug-coated balloons dominated all other options by having both lower lifetime costs and greater effectiveness. For willingness-to-pay thresholds between £0 and £100,000 per additional QALY, the probability of drug-coated balloons being cost-effective was at least 58.3 per cent for patients with IC and at least 72.2 per cent for patients with CLI. Sensitivity analyses showed that the results were robust to different assumptions regarding the clinical benefits attributable to the interventions. CONCLUSION: The use of drug-coated balloons represents a cost-effective alternative to the use of PTA with bail-out bare metal stents.
Assuntos
Angioplastia com Balão/economia , Claudicação Intermitente/economia , Stents/economia , Idoso , Amputação Cirúrgica/economia , Amputação Cirúrgica/estatística & dados numéricos , Análise Custo-Benefício , Stents Farmacológicos/economia , Humanos , Canal Inguinal/irrigação sanguínea , Claudicação Intermitente/terapia , Perna (Membro)/irrigação sanguínea , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Phosphatidylinositol transfer proteins (PITPs) have historically been thought to help execute lipid-sorting events by transporting phospholipid monomers between membrane bilayers. Recent data, however, indicate unanticipated roles for PITPs in the coordination and/or coupling of phospholipid metabolism with vesicle trafficking and the downregulation of signal-transduction reactions. We are only now beginning to appreciate both the identities of PITP-dependent cellular reactions and the intriguing mechanisms by which PITPs execute their functions in eukaryotic cells.
Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Membrana , Fosfatidilinositóis/metabolismo , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Transporte Biológico/fisiologia , Proteínas de Transporte/química , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Proteínas de Transferência de Fosfolipídeos , Saccharomyces cerevisiae/citologiaRESUMO
Receptor-activated phosphoinositide (PI) 3-kinases produce PtdIns(3, 4,5)P(3) and its metabolite PtdIns(3,4)P(2) that function as second messengers in membrane recruitment and activation of target proteins. The cytohesin and centaurin protein families are potential targets for PtdIns(3,4,5)P(3) that also regulate and interact with Arf GTPases. Consequently, these families are poised to transduce PI 3-kinase activation into coordinated control of Arf-dependent pathways. Proposed downstream events in PI 3-kinase-regulated Arf cascades include modulation of vesicular trafficking and the actin cytoskeleton.
Assuntos
Fator 1 de Ribosilação do ADP/metabolismo , Proteínas de Transporte/metabolismo , Moléculas de Adesão Celular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Fatores de Troca do Nucleotídeo Guanina , Humanos , Dados de Sequência Molecular , Fosfatos de Fosfatidilinositol/metabolismo , Transdução de SinaisRESUMO
SacIp dysfunction results in bypass of the requirement for phosphatidylinositol transfer protein (Sec14p) function in yeast Golgi processes. This effect is accompanied by alterations in inositol phospholipid metabolism and inositol auxotrophy. Elucidation of how sac1 mutants effect "bypass Sec14p" will provide insights into Sec14p function in vivo. We now report that, in addition to a dramatic accumulation of phosphatidylinositol-4-phosphate, sac1 mutants also exhibit a specific acceleration of phosphatidylcholine biosynthesis via the CDP-choline pathway. This phosphatidylcholine metabolic phenotype is sensitive to the two physiological challenges that abolish bypass Sec14p in sac1 strains; i.e. phospholipase D inactivation and expression of bacterial diacylglycerol (DAG) kinase. Moreover, we demonstrate that accumulation of phosphatidylinositol-4-phosphate in sac1 mutants is insufficient to effect bypass Sec14p. These data support a model in which phospholipase D activity contributes to generation of DAG that, in turn, effects bypass Sec14p. A significant fate for this DAG is consumption by the CDP-choline pathway. Finally, we determine that CDP-choline pathway activity contributes to the inositol auxotrophy of sac1 strains in a novel manner that does not involve obvious defects in transcriptional expression of the INO1 gene.
Assuntos
Proteínas de Bactérias/genética , Proteínas de Transporte/metabolismo , Inositol/metabolismo , Metabolismo dos Lipídeos , Proteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas de Saccharomyces cerevisiae , Leveduras/metabolismo , Proteínas de Bactérias/metabolismo , Colina/metabolismo , Cistina Difosfato/metabolismo , Diacilglicerol Quinase/metabolismo , Diglicerídeos/metabolismo , Mutação , Fosfatidilcolinas/biossíntese , Fosfatos de Fosfatidilinositol/metabolismo , Fosfolipase D/metabolismo , Proteínas de Transferência de Fosfolipídeos , Leveduras/genéticaRESUMO
The BSD2-1 allele renders Saccharomyces cerevisiae independent of its normally essential requirement for phosphatidylinositol transfer protein (Sec14p) in the stimulation of Golgi secretory function and cell viability. We now report that BSD2-1 yeast mutants also exhibit yet another phenotype, an inositol auxotrophy. We demonstrate that the basis for this Ino- phenotype is the inability of BSD2-1 strains to derepress transcription of INO1, the structural gene for the enzyme that catalyzes the committed step in de novo inositol biosynthesis in yeast. This constitutive repression of INO1 expression is mediated through specific inactivation of Ino2p, a factor required for trans-activation of INO1 transcription, and we show that these transcriptional regulatory defects can be uncoupled from the "bypass Sec14p" phenotype of BSD2-1 strains. Finally, we present evidence that newly synthesized phosphatidylinositol is subject to accelerated turnover in BSD2-1 mutants and that prevention of this accelerated phosphatidyl-inositol turnover in turn negates suppression of Sec14p defects by BSD2-1. We propose that, in BSD2-1 strains, a product(s) generated by phosphatidylinositol turnover coordinately modulates the activities of both the Sec14p/Golgi pathway and the pathway through which transcription of phospholipid biosynthetic genes is derepressed.
Assuntos
Proteínas de Transporte/genética , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Genes Fúngicos , Proteínas de Membrana , Fosfatidilinositóis/metabolismo , Fosfolipídeos/biossíntese , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Proteínas de Transporte/metabolismo , Mutação , Fosfatidilinositóis/genética , Proteínas de Transferência de Fosfolipídeos , Fosfolipídeos/genética , Saccharomyces cerevisiae/metabolismoRESUMO
Monitoring cell growth is crucial to the success of an animal cell culture process that can be accomplished by a variety of direct or indirect methodologies. Glucose is a major carbon and energy source for cultured mammalian cells in most cases, but glycolytic metabolism often results in the accumulation of lactate. Glucose and lactate levels are therefore routinely measured to determine metabolic activities of a culture. Typically, neither glucose consumption rate nor lactate accumulation rate has a direct correlation with cell density due to the changes in culture environment and cell physiology. We discovered that although the metabolic rate of glucose or lactate varies depending on the stages of a culture, the cumulative consumption of glucose and lactate combined (Q(GL)) exhibits a linear relationship relative to the integral of viable cells (IVC), with the slope indicating the specific consumption rate of glucose and lactate combined (q(GL)). Additional studies also showed that the q(GL) remains relatively constant under different culture conditions. The insensitivity of the q(GL) to process variations allows a potentially easy and accurate determination of viable cell density by the measurement of glucose and lactate. In addition, the more predictable nature of a linear relationship will aid the design of better forward control strategies to improve cell culture processes.
Assuntos
Reatores Biológicos , Células CHO/fisiologia , Técnicas de Cultura de Células/métodos , Glucose/metabolismo , Ácido Láctico/metabolismo , Monitorização Fisiológica/métodos , Animais , Proliferação de Células , Cricetinae , Cricetulus , Concentração de Íons de Hidrogênio , Taxa de Depuração Metabólica , TemperaturaRESUMO
Increasingly, PBPC instead of BM are used for autologous transplantation. Limited data exist on the economic effects of this change. Using a resource-based utilization model we prospectively determined the costs of 48 autologous transplants (eight BM, 17 BM + PBPC, 23 PBPC), isolating the post-reinfusion period (day 0 to discharge) to better determine the effect of the rescue product. Length of stay post-reinfusion was significantly shorter in patients receiving PBPC (median 13 days) or BM + PBPC (median 14 days) vs BM alone (median 20 days) (P < 0.01). Accordingly, transplant admission costs were less in the PBPC groups (PBPC $22089, BM + PBPC $23179) vs the BM alone group ($32289) (P < 0.05). Rescue product acquisition costs were higher for PBPC (range $3439-$5157) vs BM ($2766) but these costs were offset by the more rapid recovery of patients receiving PBPC. Overall transplant costs depend on the conditioning regimen with a 10-fold cost variation among regimens. Modeled costs for autologus transplantation using various approaches to rescue product acquisition are given. The introduction of PBPC for autologus transplantation has resulted in cost savings at our institution. Although the acquisition costs of PBPC rescue product are greater than for BM, this incremental expense is more than offset by a less expensive post-reinfusion period.
Assuntos
Transplante de Medula Óssea/economia , Custos de Cuidados de Saúde , Transplante de Células-Tronco Hematopoéticas/economia , Adolescente , Adulto , Transfusão de Sangue/economia , Transfusão de Sangue/estatística & dados numéricos , Custos e Análise de Custo , Feminino , Fator Estimulador de Colônias de Granulócitos/economia , Mobilização de Células-Tronco Hematopoéticas/economia , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Terapia de Salvação , Condicionamento Pré-Transplante/economia , Transplante Autólogo/economiaRESUMO
We describe a biotin-avidin based rate turbidimetric homogeneous immunoassay for the determination of serum theophylline with a measuring range of 0-40 micrograms/ml. The assay features an avidin-biotin-labeled theophylline conjugate and a monoclonal antibody. The rate of change of turbidity caused by the antibody-conjugate complexing was monitored on the Beckman Synchron CX 4 System at 340 nm and 37 degrees C. Theophylline in a sample inhibited the complexation, and the extent of inhibition allowed the quantitation of theophylline in the sample. The within-run coefficient of variation (CV) was < 3.7% and the between-run CV was 5.2-9.2% depending on the theophylline concentration. Linear regression analysis showed a good correlation with an established fluorescence polarization immunoassay (r = 0.9866, n = 94).
Assuntos
Imunoensaio/métodos , Nefelometria e Turbidimetria/métodos , Teofilina/sangue , Avidina , Biotina , Estudos de Avaliação como Assunto , Imunoensaio de Fluorescência por Polarização , Humanos , Imunoensaio/estatística & dados numéricos , Nefelometria e Turbidimetria/estatística & dados numéricos , Sensibilidade e EspecificidadeAssuntos
Proteínas de Transporte/fisiologia , Moléculas de Adesão Celular/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Proteínas Virais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfatos de Fosfatidilinositol/metabolismoRESUMO
BACKGROUND: Acute deep vein thrombosis has traditionally been treated with unfractionated heparin (UFH), administered intravenously, but low-molecular-weight heparins (LMWH), administered subcutaneously, have recently become available. The authors sought to determine which therapy was more cost-effective for inpatient and outpatient treatment of deep vein thrombosis. METHODS: An incremental cost-effectiveness analysis based on a decision tree was performed for 4 treatment strategies for deep vein thrombosis. Rate of major hemorrhage while receiving heparin, rate of recurrence of venous thromboembolism 3 months after treatment and mortality rate 3 months after treatment were determined by meta-analysis. Costs for the UFH therapy were prospectively collected by a case-costing accounting system for 105 patients with deep vein thrombosis treated in fiscal year 1995/96. The costs for LMWH therapy were modelled, and cost-effectiveness was determined by decision analysis. RESULTS: Meta-analysis revealed a mean difference in risk of hemorrhage of -1.1% (95% confidence interval [CI] -2.4% to 0.3%), a mean difference in risk of recurrence of venous thromboembolism of -2.6% (95% CI -4.5% to -0.7%) and a mean difference in risk of death of -1.9% (95% CI -3.6% to -0.4%), all in favour of subcutaneous unmonitored administration of LMWH. The cost to treat one inpatient was $2993 for LMWH and $3048 for UFH. Even more would be saved if LMWH was delivered on an outpatient basis (cost of $1641 per patient). The cost-effectiveness analysis showed that LMWH in any treatment setting is more cost effective than UFH. A sensitivity analysis demonstrated the robustness of this conclusion. INTERPRETATION: Treatment of deep vein thrombosis with LMWH is more cost effective than treatment with UFH in both inpatient and outpatient settings.
Assuntos
Custos de Medicamentos , Heparina de Baixo Peso Molecular/economia , Heparina/economia , Trombose Venosa/tratamento farmacológico , Trombose Venosa/economia , Canadá , Análise Custo-Benefício , Árvores de Decisões , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Resultado do TratamentoRESUMO
The objective was to describe the epidemiologic, clinical, bacteriologic and therapeutic features of seven infants who developed sternal wound and mediastinal infections following palliation and/or repair procedures for congenital heart disease. A retrospective chart review was used. All infants with sternal wound and mediastinal infections were < 30 days of age at the initial operative procedure. Six of the infants had hypoplastic left heart syndrome, and one had complete transposition. Two infants required delayed closure of their chest wound. Three infants had superficial sternal infections and presented at a mean of 12 days postoperatively. Four infants had infection of the deep mediastinal structures: they were all asymptomatic and had purulent collections in their mediastinum at their second palliative operation, which was performed at a mean of 120 days after the initial surgery. Staphylococcus aureus, or coagulase-negative Staphylococcus, was isolated from the wound and/or blood of six infants. All infants with mediastinal infections were managed with operative debridement. Infants with superficial infections underwent local debridement. All infants received long-term intravenous antibiotics. Mediastinal infections in infants undergoing palliative staged procedures for congenital heart lesions may be chronic and indolent, resulting in delayed repair of congenital heart lesions.
Assuntos
Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Doenças do Mediastino/etiologia , Infecção da Ferida Cirúrgica/etiologia , Transposição dos Grandes Vasos/cirurgia , Desbridamento , Feminino , Humanos , Recém-Nascido , Masculino , Doenças do Mediastino/cirurgia , Estudos Retrospectivos , Esterno , Infecção da Ferida Cirúrgica/cirurgiaRESUMO
To identify potential Sec4 effectors, we isolated high copy suppressors of a Sec4 effector domain mutant. The most potent of these was found to be SEC9, a gene required for post-Golgi transport. The sole essential domain of Sec9 has significant sequence similarity to the neuronal protein SNAP-25, a component of the SNARE complex, that is implicated in vesicle targeting and fusion. Analogous to SNAP-25, Sec9 is bound to the yeast plasma membrane and is absent from post-Golgi vesicles. Furthermore, Sec9 is physically associated with two proteins that are homologous to components of the neuronal SNARE complex. Our results identify Sec9 as the yeast cognate of SNAP-25 and suggest that SNARE complexes acting at specific stages of vesicular transport serve as the ultimate targets of regulation by members of the Sec4/Ypt1/Rab family of GTPases.
Assuntos
Exocitose , Proteínas Fúngicas/fisiologia , Proteínas de Ligação ao GTP/fisiologia , Proteínas de Saccharomyces cerevisiae , Proteínas rab de Ligação ao GTP , Sequência de Aminoácidos , Membrana Celular/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteínas Qa-SNARE , Proteínas Qc-SNARE , Proteínas R-SNARE , Saccharomyces cerevisiae , Relação Estrutura-Atividade , Proteína 25 Associada a SinaptossomaRESUMO
Analysis of microsomal ATP transport in yeast resulted in the identification of Sac1p as an important factor in efficient ATP uptake into the endoplasmic reticulum (ER) lumen. Yet it remained unclear whether Sac1p is the authentic transporter in this reaction. Sac1p shows no homology to other known solute transporters but displays similarity to the N-terminal non-catalytic domain of a subset of inositol 5'-phosphatases. Furthermore, Sac1p was demonstrated to be involved in inositol phospholipid metabolism, an activity whose absence contributes to the bypass Sec14p phenotype in sac1 mutants. We now show that purified recombinant Sac1p can complement ATP transport defects when reconstituted together with sac1Delta microsomal extracts, but is unable to catalyze ATP transport itself. In addition, we demonstrate that sac1Delta strains are defective in ER protein translocation and folding, which is a direct consequence of impaired ATP transport function and not related to the role of Sac1p in Golgi inositol phospholipid metabolism. These data suggest that Sac1p is an important regulator of microsomal ATP transport providing a possible link between inositol phospholipid signaling and ATP-dependent processes in the yeast ER.
Assuntos
Trifosfato de Adenosina/metabolismo , Proteínas Fúngicas/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Microssomos/metabolismo , Fosfolipídeos/metabolismo , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Retículo Endoplasmático/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Cinética , Lipossomos/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Dados de Sequência Molecular , Monoéster Fosfórico Hidrolases , Proteolipídeos/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimentoRESUMO
Although many hematologic malignancies are more common in older patients, autologous blood and marrow transplantation (ABMT) has traditionally been restricted to patients younger than 60 years because of concerns that older patients would be either unable to provide a graft or unable to tolerate the therapy. From June 1995 to May 1998, 30 patients > or = 60 years underwent ABMT at our institution for low-grade lymphoma (4 patients), relapsed intermediate-grade lymphoma (17 patients), or multiple myeloma (9 patients). The median patient age was 62.5 years (range 60-73). Pretransplantation conditioning regimens were CBV (cyclophosphamide, BCNU [carmustine], etoposide) or BEAM (carmustine, etoposide, cytarabine, melphalan) for intermediate-grade lymphoma patients and melphalan 140 mg/m2 + etoposide 60 mg/kg + total body irradiation 500 cGy for the others. The rescue product was bone marrow (BM; 4 patients), peripheral blood stem cells (PBSC; 23 patients), or BM+PBSC (3 patients). The median number of CD34+ cells/kg infused was 3.60 x 10(6) (range 0.53-31.0), by the International Society for Hematotherapy and Graft Engineering method. The treatment-related mortality at day 100 and at 6 months was 10% and 16.7%, respectively. The median days to neutrophil > 0.5 x 10(9)/L was 11 (range 9-25) and platelets > 20 x 10(9)/L was 16 (range 6-70). Three patients died of infection (days 26, 27, and 38), and 1 died of an intracranial hemorrhage related to persistent thrombocytopenia (day 130). Bearman regimen-related toxicity was moderate, with most toxicities < or = grade 2. Seven patients developed significant gut toxicity: 4 patients with Clostridium difficile colitis and 3 patients with neutropenic enterocolitis. Depressive symptoms and signs were noted in 4 patients. Three male patients developed decreased gonadal function after transplantation. These transplantations accounted for 997 patient days, of which 266 days (27%) were in the outpatient BMT program--a smaller percentage than in patients < 60 years (56%, P = .002). Twenty patients are alive 153 to > or = 1224 days after transplantation. ABMT in patients > or = 60 years of age is feasible. Further studies addressing supportive care particular to older patients and comparisons of ABMT with traditional approaches to multiple myeloma and relapsed non-Hodgkin's lymphoma in older patients are needed. Further work to identify elderly patients most likely to benefit from this approach is also required.
Assuntos
Transplante Autólogo/efeitos adversos , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Transplante de Medula Óssea/efeitos adversos , Feminino , Febre , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospitalização , Humanos , Infecções/etiologia , Linfoma/complicações , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/terapia , Terapia de Salvação/efeitos adversos , Taxa de Sobrevida , Trombocitopenia/etiologia , Resultado do TratamentoRESUMO
Yeast phosphatidylinositol transfer protein (Sec14p) is required for the production of secretory vesicles from the Golgi. This requirement can be relieved by inactivation of the cytosine 5'-diphosphate (CDP)-choline pathway for phosphatidylcholine biosynthesis, indicating that Sec14p is an essential component of a regulatory pathway linking phospholipid metabolism with vesicle trafficking (the Sec14p pathway). Sac1p (refs 7 and 8) is an integral membrane protein related to inositol-5-phosphatases such as synaptojanin, a protein found in rat brain. Here we show that defects in Sac1p also relieve the requirement for Sec14p by altering phospholipid metabolism so as to expand the pool of diacylglycerol (DAG) in the Golgi. Moreover, although short-chain DAG improves secretory function in strains with a temperature-sensitive Sec14p, expression of diacylglycerol kinase from Escherichia coli further impairs it. The essential function of Sec14p may therefore be to maintain a sufficient pool of DAG in the Golgi to support the production of secretory vesicles.
Assuntos
Proteínas de Transporte/metabolismo , Diglicerídeos/metabolismo , Proteínas Fúngicas/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Transporte Biológico , Clonagem Molecular , Diacilglicerol Quinase , Escherichia coli , Proteínas Fúngicas/genética , Glicosídeo Hidrolases/metabolismo , Membranas Intracelulares/metabolismo , Proteínas de Membrana/genética , Mutagênese , Fosfatidilinositóis/metabolismo , Proteínas de Transferência de Fosfolipídeos , Monoéster Fosfórico Hidrolases , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Esfingolipídeos/metabolismo , beta-FrutofuranosidaseRESUMO
The yeast phosphatidylinositol transfer protein (Sec14p) is required for biogenesis of Golgi-derived transport vesicles and cell viability, and this essential Sec14p requirement is abrogated by inactivation of the CDP-choline pathway for phosphatidylcholine biosynthesis. These findings indicate that Sec14p functions to alleviate a CDP-choline pathway-mediated toxicity to yeast Golgi secretory function. We now report that this toxicity is manifested through the action of yeast Kes1p, a polypeptide that shares homology with the ligand-binding domain of human oxysterol binding protein (OSBP). Identification of Kes1p as a negative effector for Golgi function provides the first direct insight into the biological role of any member of the OSBP family, and describes a novel pathway for the regulation of Golgi-derived transport vesicle biogenesis.
Assuntos
Proteínas Fúngicas/metabolismo , Complexo de Golgi/fisiologia , Proteínas de Membrana , Receptores de Esteroides/química , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/fisiologia , Saccharomyces cerevisiae/ultraestrutura , Alelos , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação , Proteínas de Transporte/metabolismo , Citidina Difosfato Colina/metabolismo , Primers do DNA , Proteínas Fúngicas/química , Complexo de Golgi/ultraestrutura , Humanos , Fosfatidilinositóis/metabolismo , Proteínas de Transferência de Fosfolipídeos , Reação em Cadeia da Polimerase , Proteínas Recombinantes/metabolismo , Homologia de Sequência de AminoácidosRESUMO
The Saccharomyces cerevisiae SAC1 gene was identified via independent analyses of mutations that modulate yeast actin function and alleviate the essential requirement for phosphatidylinositol transfer protein (Sec14p) activity in Golgi secretory function. The SAC1 gene product (Sac1p) is an integral membrane protein of the endoplasmic reticulum and the Golgi complex. Sac1p shares primary sequence homology with a subfamily of cytosolic/peripheral membrane phosphoinositide phosphatases, the synaptojanins, and these Sac1 domains define novel phosphoinositide phosphatase modules. We now report the characterization of a rat counterpart of Sac1p. Rat Sac1 is a ubiquitously expressed 65-kDa integral membrane protein of the endoplasmic reticulum that is found at particularly high levels in cerebellar Purkinje cells. Like Sac1p, rat Sac1 exhibits intrinsic phosphoinositide phosphatase activity directed toward phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, and phosphatidylinositol 3,5-bisphosphate substrates, and we identify mutant rat sac1 alleles that evoke substrate-specific defects in this enzymatic activity. Finally, rat Sac1 expression in Deltasac1 yeast strains complements a wide phenotypes associated with Sac1p insufficiency. Biochemical and in vivo data indicate that rat Sac1 phosphatidylinositol-4-phosphate phosphatase activity, but not its phosphatidylinositol-3-phosphate or phosphatidylinositol-3, 5-bisphosphate phosphatase activities, is essential for the heterologous complementation of Sac1p defects in vivo. Thus, yeast Sac1p and rat Sac1 are integral membrane lipid phosphatases that play evolutionary conserved roles in eukaryotic cell physiology.