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This is a case of a 61-year-old lady who presented to the lipid clinic with possible familial hypercholesterolaemia (Simon Broome Criteria). She was commenced on atorvastatin; however, 4 weeks later, she developed hepatitis, and therefore her atorvastatin was discontinued. Following that, her liver function tests normalized, and she was diagnosed with statin-induced hepatitis. Three years later, she was seen again in the lipid clinic with an uncontrolled lipid profile, and she was commenced on alirocumab, a Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitor. A few days later, she developed hepatitis, and subsequently, the alirocumab was discontinued. She underwent a liver biopsy, which confirmed that she had Autoimmune Hepatitis (AIH) with presumed superimposed drug injury. This is the first reported case of autoimmune hepatitis associated with alirocumab.
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BACKGROUND: Cardiopulmonary exercise testing (CPET) may provide prognostically valuable information during follow-up after pulmonary embolism (PE). Our objective was to investigate the association of patterns and degree of exercise limitation, as assessed by CPET, with clinical, echocardiographic and laboratory abnormalities and quality of life (QoL) after PE. METHODS: In a prospective cohort study of unselected consecutive all-comers with PE, survivors of the index acute event underwent 3- and 12-month follow-ups, including CPET. We defined cardiopulmonary limitation as ventilatory inefficiency or insufficient cardiocirculatory reserve. Deconditioning was defined as peak O2 uptake (V'O2 ) <80% with no other abnormality. RESULTS: Overall, 396 patients were included. At 3â months, prevalence of cardiopulmonary limitation and deconditioning was 50.1% (34.7% mild/moderate; 15.4% severe) and 12.1%, respectively; at 12â months, it was 44.8% (29.1% mild/moderate; 15.7% severe) and 14.9%, respectively. Cardiopulmonary limitation and its severity were associated with age (OR per decade 2.05, 95% CI 1.65-2.55), history of chronic lung disease (OR 2.72, 95% CI 1.06-6.97), smoking (OR 5.87, 95% CI 2.44-14.15) and intermediate- or high-risk acute PE (OR 4.36, 95% CI 1.92-9.94). Severe cardiopulmonary limitation at 3â months was associated with the prospectively defined, combined clinical-haemodynamic end-point of "post-PE impairment" (OR 6.40, 95% CI 2.35-18.45) and with poor disease-specific and generic health-related QoL. CONCLUSIONS: Abnormal exercise capacity of cardiopulmonary origin is frequent after PE, being associated with clinical and haemodynamic impairment as well as long-term QoL reduction. CPET can be considered for selected patients with persisting symptoms after acute PE to identify candidates for closer follow-up and possible therapeutic interventions.
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Teste de Esforço , Embolia Pulmonar , Humanos , Qualidade de Vida , Seguimentos , Estudos Prospectivos , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/terapia , Doença Aguda , Tolerância ao ExercícioRESUMO
The apical junction of epithelial cells can generate force to control cell geometry and perform contractile processes while maintaining barrier function and adhesion. Yet, the structural basis for force generation at the apical junction is not fully understood. Here, we describe two synaptopodin-dependent actomyosin structures that are spatially, temporally, and structurally distinct. The first structure is formed by the retrograde flow of synaptopodin initiated at the apical junction, creating a sarcomeric stress fiber that lies parallel to the apical junction. Contraction of the apical stress fiber is associated with either clustering of membrane components or shortening of junctional length. Upon junction maturation, apical stress fibers are disassembled. In mature epithelial monolayer, a motorized "contractomere" capable of "walking the junction" is formed at the junctional vertex. Actomyosin activities at the contractomere produce a compressive force evident by actin filament buckling and measurement with a new α-actinin-4 force sensor. The motility of contractomeres can adjust junctional length and change cell packing geometry during cell extrusion and intercellular movement. We propose a model of epithelial homeostasis that utilizes contractomere motility to support junction rearrangement while preserving the permeability barrier.
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Actomiosina , Células Epiteliais , Junções Intercelulares , Proteínas dos Microfilamentos , Fibras de Estresse , Citoesqueleto de Actina/metabolismo , Actomiosina/metabolismo , Células Epiteliais/metabolismo , Junções Intercelulares/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fibras de Estresse/metabolismoRESUMO
[Figure: see text].
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Coagulação Sanguínea/efeitos dos fármacos , Produtos de Degradação da Fibrina e do Fibrinogênio/farmacologia , Leucócitos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Veia Cava Inferior/metabolismo , Trombose Venosa/sangue , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Estudos de Casos e Controles , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Humanos , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/sangue , Embolia Pulmonar/sangue , Células THP-1 , Fatores de Tempo , Veia Cava Inferior/patologia , Trombose Venosa/patologiaRESUMO
Smoking is known to increase the risk of peri-operative complications in Orthoplastic surgery by impairing bone and wound healing. The effects of nicotine replacement therapies (NRTs) and electronic cigarettes (e-cigarettes) has been less well established. Previous reviews have examined the relationship between smoking and bone and wound healing separately. This review provides surgeons with a comprehensive and contemporaneous account of how smoking in all forms interacts with all aspects of complex lower limb trauma. We provide a guide for surgeons to refer to during the consent process to enable them to tailor information towards smokers in such a way that the patient may understand the risks involved with their surgical treatment. We update the literature with recently discovered methods of monitoring and treating the troublesome complications that occur more commonly in smokers effected by trauma.
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Sistemas Eletrônicos de Liberação de Nicotina , Abandono do Hábito de Fumar , Humanos , Extremidade Inferior/cirurgia , Fumar/efeitos adversos , Dispositivos para o Abandono do Uso de TabacoRESUMO
Primary patellar neoplasms are rare, comprising 0.12% of primary bone tumours; thus, no standardised treatment related to staging exists. 70%-90% of primary patellar neoplasms are benign or intermediate with giant cell tumour (GCT) being the most common. GCTs are locally aggressive, have a high recurrence rate and metastasise in 1%-2%. We report the case of a 23-year-old man with histologically confirmed recurrent GCT of the patella to demonstrate that aggressive surgical management options described in the literature, such as patellectomy with or without complex reconstruction, may be excessive and cause patients undue morbidity. Initially, the patient underwent intralesional curettage with excellent recovery, but presented again with a local recurrence within a year. A further definitive operation was performed which included excision of the inferior pole followed by curettage of the patellar body and artificial bone grafting. The patient made a good recovery and at 5-year follow-up has maintained good function.
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Neoplasias Ósseas/diagnóstico por imagem , Carcinoma de Células Gigantes/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Patela/diagnóstico por imagem , Neoplasias Ósseas/cirurgia , Transplante Ósseo/métodos , Carcinoma de Células Gigantes/cirurgia , Curetagem/métodos , Humanos , Imageamento por Ressonância Magnética , Masculino , Recidiva Local de Neoplasia/cirurgia , Patela/cirurgia , Radiografia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The incidence of spina bifida (SB) is â¼1:1000, and risk of stone disease is substantially raised in SB. This is the unique published study of the outcome of patients with SB undergoing percutaneous nephrolithotomy (PCNL) compared to a neurologically intact historically matched control group at the same institution. PATIENTS AND METHOD: A series of 96 PCNLs in 13 SB and 50 non-SB patients was analyzed. The following measurements were recorded: (1) Comorbidities; (2) Preoperative: (renal function, American Society of Anesthesiologists [ASA] score); (3) Intraoperative: (anesthesia time, number of tracks, stone-free rate); and (4) Postoperative: (sepsis, intensive therapy unit and total length of stay, transfusion rate, stone composition, rate of stone disease-related nephrectomy). RESULTS: Retrograde access to the ureter was impossible in all cases of SB. The median ASA grade (OR 10.5, 95% confidence interval [CI] 2.6-42.7) and operative time (median difference 30 minutes, 95% CI 20-40) were both higher in the SB cohort. Surgeon's estimate of stone-free rate was significantly lower in the SB cohort (46% vs 82%). Intensive care requirement (0.29 days/PCNL vs 0.1 days/PCNL); total hospital stay (7 days vs 4 days); postoperative transfusion rate (11.8% vs 1.6%); and sepsis rate (38% vs 1.6%) were all significantly higher in the SB group. Repeat PCNL and nephrectomy for recurrent stone disease were both significantly increased in SB cohort compared to control group. CONCLUSIONS: PCNL in patients with SB is associated with multiple parameters of poor outcome. Patients with SB should be counseled about increased peri-operative risk and likelihood of stone recurrence. In an era where hospitals are judged according to comparative outcomes, a case may be made for comparing PCNL in this cohort of patients separately because of the significantly increased peri- and postoperative morbidity.
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Cálculos Renais/cirurgia , Nefrolitotomia Percutânea/métodos , Disrafismo Espinal/complicações , Adulto , Idoso , Anestesia , Anestesiologia , Transfusão de Sangue/estatística & dados numéricos , Estudos de Casos e Controles , Feminino , Hospitais , Humanos , Incidência , Cálculos Renais/patologia , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Nefrectomia/estatística & dados numéricos , Nefrostomia Percutânea/efeitos adversos , Duração da Cirurgia , Recidiva , Estudos Retrospectivos , Sepse/etiologiaRESUMO
Addressing the global burden of cancer, understanding its diverse biology, and promoting appropriate prevention and treatment strategies around the world has become a priority for the United Nations and International Atomic Energy Agency (IAEA), the WHO, and International Agency for Research on Cancer (IARC). The IAEA sponsored an international prospective cohort study to better understand biology, treatment response, and outcomes of diffuse large B-cell lymphoma (DLBCL) in low and middle-income countries across five UN-defined geographical regions. We report an analysis of biological variation in DLBCL across seven ethnic and environmentally diverse populations. In this cohort of 136 patients treated to a common protocol, we demonstrate significant biological differences between countries, characterized by a validated prognostic gene expression score (p < .0001), but International Prognostic Index (IPI)-adjusted survivals in all participating countries were similar. We conclude that DLBCL treatment outcomes in these populations can be benchmarked to international standards, despite biological heterogeneity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/epidemiologia , Adulto , Idoso , Anticorpos Monoclonais Murinos/uso terapêutico , Biomarcadores Tumorais , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Saúde Global , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade , Vigilância da População , Prednisona/uso terapêutico , Prognóstico , Rituximab , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
With the cell therapy industry continuing to grow, the ability to preserve clinical grade cells, including mesenchymal stem cells (MSCs), whilst retaining cell viability and function remains critical for the generation of off-the-shelf therapies. Cryopreservation of MSCs, using slow freezing, is an established process at lab scale. However, the cytotoxicity of cryoprotectants, like Me2SO, raises questions about the impact of prolonged cell exposure to cryoprotectant at temperatures >0 °C during processing of large cell batches for allogenic therapies prior to rapid cooling in a controlled rate freezer or in the clinic prior to administration. Here we show that exposure of human bone marrow derived MSCs to Me2SO for ≥1 h before freezing, or after thawing, degrades membrane integrity, short-term cell attachment efficiency and alters cell immunophenotype. After 2 h's exposure to Me2SO at 37 °C post-thaw, membrane integrity dropped to â¼70% and only â¼50% of cells retained the ability to adhere to tissue culture plastic. Furthermore, only 70% of the recovered MSCs retained an immunophenotype consistent with the ISCT minimal criteria after exposure. We also saw a similar loss of membrane integrity and attachment efficiency after exposing osteoblast (HOS TE85) cells to Me2SO before, and after, cryopreservation. Overall, these results show that freezing medium exposure is a critical determinant of product quality as process scale increases. Defining and reporting cell sensitivity to freezing medium exposure, both before and after cryopreservation, enables a fair judgement of how scalable a particular cryopreservation process can be, and consequently whether the therapy has commercial feasibility.
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Criopreservação/métodos , Crioprotetores/farmacologia , Dimetil Sulfóxido/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Congelamento , Humanos , Células-Tronco Mesenquimais/citologiaRESUMO
BACKGROUND: We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics. METHODS: We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence. RESULTS: For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava filter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C). CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research.
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Medicina Baseada em Evidências/normas , Fibrinolíticos/uso terapêutico , Sociedades Médicas , Trombose Venosa/tratamento farmacológico , Esquema de Medicação , Fibrinolíticos/administração & dosagem , Humanos , Coeficiente Internacional Normatizado , Trombose Venosa/sangueRESUMO
BACKGROUND: The purpose of this study was to investigate the ocular bacterial flora in patients scheduled to undergo cataract surgery and compare the antibacterial effects of besifloxacin ophthalmic suspension 0.6% and moxifloxacin ophthalmic solution 0.5% in these patients. METHODS: This was a prospective, randomized, laboratory-masked clinical trial. Patients received besifloxacin or moxifloxacin "quater in die" or QID (four times a day) for 3 days before cataract surgery in the surgical eye and 1 hour before surgery in the nonsurgical fellow eye. Conjunctival and eyelid swabs were obtained from both eyes at baseline and after treatment, on the day of surgery (Visit 2). Swabs were processed for bacterial colony counts (in terms of colony-forming units) and species identification. In vitro antibiotic susceptibilities of isolates were determined using Clinical and Laboratory Standards Institute breakpoints. RESULTS: Fifty-nine patients (n=28 besifloxacin, n=31 moxifloxacin) completed the study. The majority (73%) of conjunctival samples were culture negative at baseline. The most frequent isolates were coagulase-negative staphylococci (CoNS, 89%), specifically Staphylococcus epidermidis (72%). Both fluoroquinolones reduced the lid CFU values when administered QID for 3 days (P≤0.019), but only besifloxacin reduced the lid CFU estimate 1 hour following instillation of a single drop (P=0.039). Fewer besifloxacin-treated eyes had lids that were culture positive for CoNS at Visit 2 compared with moxifloxacin-treated eyes regardless of dosing regimen (P≤0.03). The minimum inhibitory concentration (MIC90) of besifloxacin against methicillin-resistant S. epidermidis (MRSE) was eightfold lower than that of moxifloxacin. CONCLUSION: Besifloxacin appeared more effective in reducing bacterial counts on eyelids of patients undergoing cataract surgery, with significant reductions as early as 1 hour postdose, compared with moxifloxacin. Besifloxacin was more active in vitro against MRSE.
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OBJECTIVE: We performed a randomised trial in very preterm, small for gestational age (SGA) babies to determine if prophylaxis with granulocyte macrophage colony stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). GM-CSF was associated with improved neonatal neutrophil counts, but no change in other neonatal or 2-year outcomes. As subtle benefits in outcome may not be ascertainable until school age we performed an outcome study at 5â years. PATIENTS AND METHODS: 280 babies born at 31â weeks of gestation or less and SGA were entered into the trial. Outcomes were assessed at 5â years to determine neurodevelopmental and general health status and educational attainment. RESULTS: We found no significant differences in cognitive, general health or educational outcomes between 83 of 106 (78%) surviving children in the GM-CSF arm compared with 81 of 110 (74%) in the control arm. Mean mental processing composite (equivalent to IQ) at 5â years were 94 (SD 16) compared with 95 (SD 15), respectively (difference in means -1 (95%CI -6 to 4), and similar proportions were in receipt of special educational needs support (41% vs 35%; risk ratio 1.2 (95% CI 0.8 to 1.9)). Performance on Kaufmann-ABC subscales and components of NEPSY were similar. The suggestion of worse respiratory outcomes in the GM-CSF group at 2â years was replicated at 5â years. CONCLUSIONS: The administration of GM-CSF to very preterm SGA babies is not associated with improved or more adverse neurodevelopmental, general health or educational outcomes at 5â years. TRIAL REGISTRATION NUMBER: ISRCTN42553489.
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Desenvolvimento Infantil/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Lactente Extremamente Prematuro , Recém-Nascido Pequeno para a Idade Gestacional , Sepse/prevenção & controle , Feminino , Fármacos Hematológicos/administração & dosagem , Humanos , Lactente Extremamente Prematuro/sangue , Lactente Extremamente Prematuro/crescimento & desenvolvimento , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/sangue , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Contagem de Leucócitos , Masculino , Testes Neuropsicológicos , Neutrófilos , Avaliação de Resultados em Cuidados de Saúde , TempoRESUMO
AIM: Adalimumab is an effective treatment for Crohn's disease (CD). We aimed to describe the early patterns of use, efficacy and response to adalimumab in four regions of New Zealand. METHODS: Prospectively collected CDAI data were used to examine adalimumab continuation rates in CD patients. Reasons for adalimumab cessation were determined and phenotypic characteristics of those remaining on adalimumab were examined. RESULTS: 194 patients (100 female) from four centres were included. Indications for adalimumab included CDAI>300 (59.8%), extensive small intestinal disease (21.1%), stoma with active disease (4.6%), risk of short gut syndrome (7.7%) and other (6.7%). The mean follow-up was 20 months (252.8 patient years of data). Adalimumab continuation rates at 6, 12, 24 and 30 months were 92.7%, 87.3%, 76.6% and 67.4%, respectively. Patients with penetrating disease behaviour were more likely to continue on adalimumab (p<0.005). There was a significant reduction in mean CDAI from 357 to 110 (p<0.0001) over a 6-month period. The mean (range) number of days spent in hospital per patient in the year prior and after adalimumab initiation were 3.5 (0-38) days and 1.9 (0-67) days, respectively (p<0.0001). CONCLUSIONS: Adalimumab continuation rate in this multicentre CD population was higher than other populations. This may be due to adalimumab being used more commonly as the initial biologic drug in New Zealand.
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Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/tratamento farmacológico , Adalimumab , Adulto , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Humanos , Masculino , Adesão à Medicação , Nova Zelândia , Períneo , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: The authors performed a randomised trial in very preterm small-for-gestational age (SGA) babies to determine if prophylaxis with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). Despite increased neutrophil counts following GM-CSF, the authors reported no significant difference in neonatal sepsis-free survival. PATIENTS AND METHODS: 280 babies born <31 weeks of gestation and SGA were entered into the trial. Outcome was determined at 2 years to determine neurodevelopmental and general health outcomes, including economic costs. RESULTS: The authors found no significant differences in health outcomes or health and social care costs between the trial groups. In the GM-CSF arm, 87 of 134 (65%) babies survived to 2 years without severe disability compared with 87 of 131 (66%) controls (RR: 1·0, 95% CI 0·8 to 1·2). Marginally, more children receiving GM-CSF were reported to have cough (RR 1·7, 95% CI 1·1 to 2·6) and had signs of chronic respiratory disease (Harrison's sulcus; RR 2·0, 95% CI 1·0 to 3·9) though this was not reflected in bronchodilator use or need for hospitalisation for respiratory disease. Overall, the rate of neurologic abnormality (7%-9%) was similar but mean overall developmental scores were lower than expected for gestational age. CONCLUSIONS: The administration of GM-CSF to very preterm SGA babies is not associated with improved or more adverse outcomes at 2 years of age. The apparent excess of developmental impairment in the entire PROGRAMS cohort, without corresponding increase in neurological abnormality, may represent diffuse brain injury attributable to intrauterine growth restriction.
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Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Lactente Extremamente Prematuro , Doenças do Prematuro/prevenção & controle , Recém-Nascido Pequeno para a Idade Gestacional , Sepse/prevenção & controle , Deficiências do Desenvolvimento/epidemiologia , Crianças com Deficiência/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Humanos , Recém-Nascido , Doenças do Prematuro/mortalidade , Masculino , Sepse/mortalidadeRESUMO
PURPOSE AND EXPERIMENTAL DESIGN: Recombinant human IL-2 (rhIL-2) is a potent cytokine and FDA-approved anticancer drug. However, its clinical use has been limited by severe toxicity, associated primarily with systemic administration with excess protein distributing freely throughout the body. We hypothesized that rhIL-2 in alternate forms permitting more restricted localization may exert stronger antitumor efficacy and less toxicity. Here, we have tested the utility of palmitate-derivatized rhIL-2. rhIL-2 was reacted with N-hydroxysuccinimide palmitate ester. The resultant lipidated rhIL-2 (pIL-2), when mixed with cells, could spontaneously transfer from solution to cell surfaces. Next, anticancer efficacy of pIL-2 was assessed in two modalities. For adoptive T cell therapy, antitumor cytotoxic T cells (CTLs) were protein transferred ("painted") with pIL-2 and injected into mice bearing lymphoma. For in situ therapy, pIL-2 was injected intratumorally into mice bearing melanoma. Tumor growth and IL-2-associated toxicity were determined. RESULTS: In the lymphoma model, painting of the antitumor CTLs with pIL-2 markedly increased their viability and titer. In the melanoma model, intratumoral injection of pIL-2, but not rhIL-2, increased the number of activated CD8(+) T cells (IFN-γ(+)) in the spleen, reduced lung metastasis and prolonged the survival of treated mice. Moreover, while repeated intratumoral injection of rhIL-2 at an excessively high dose (10 injections of 10,000 IU/mouse) caused marked vascular leakage syndrome, the same regimen using pIL-2 caused no detectable toxicity. CONCLUSIONS: Transferring spontaneously from solution to cell surfaces, pIL-2 may bypass the current limitations of rhIL-2 and, thus, serve as a more effective and tolerable anticancer drug.
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Imunoterapia Adotiva/métodos , Interleucina-2/administração & dosagem , Linfoma/terapia , Melanoma Experimental/terapia , Proteínas Recombinantes/administração & dosagem , Animais , Humanos , Interleucina-2/efeitos adversos , Interleucina-2/genética , Camundongos , Camundongos Transgênicos , Ácido Palmítico , Proteínas Recombinantes/efeitos adversos , Succinimidas , Linfócitos T Citotóxicos/transplanteRESUMO
BACKGROUND: Hospitalized smokers often quit smoking, voluntarily or involuntarily; most relapse soon after discharge. Extended follow-up counseling can help prevent relapse. However, it is difficult for hospitals to provide follow-up and smokers rarely leave the hospital with quitting aids (for example, nicotine patches). This study aims to test a practical model in which hospitals work with a state cessation quitline. Hospital staff briefly intervene with smokers at bedside and refer them to the quitline. Depending on assigned condition, smokers may receive nicotine patches at discharge or extended quitline telephone counseling post-discharge. This project establishes a practical model that lends itself to broader dissemination, while testing the effectiveness of the interventions in a rigorous randomized trial. METHODS/DESIGN: This randomized clinical trial (N = 1,640) tests the effect of two interventions on long-term quit rates of hospitalized smokers in a 2 x 2 factorial design. The interventions are (1) nicotine patches (eight-week, step down program) dispensed at discharge and (2) proactive telephone counseling provided by the state quitline after discharge. Subjects are randomly assigned into: usual care, nicotine patches, telephone counseling, or both patches and counseling. It is hypothesized that patches and counseling have independent effects and their combined effect is greater than either alone. The primary outcome measure is thirty-day abstinence at six months; a secondary outcome is biochemically validated smoking status. Cost-effectiveness analysis is conducted to compare each intervention condition (patch alone, counseling alone, and combined interventions) against the usual care condition. Further, this study examines whether smokers' medical diagnosis is a moderator of treatment effect. Generalized linear (binomial) mixed models will be used to study the effect of treatment on abstinence rates. Clustering is accounted for with hospital-specific random effects. DISCUSSION: If this model is effective, quitlines across the U.S. could work with interested hospitals to set up similar systems. Hospital accreditation standards related to tobacco cessation performance measures require follow-up after discharge and provide additional incentive for hospitals to work with quitlines. The ubiquity of quitlines, combined with the consistency of quitline counseling delivery as centralized state operations, make this partnership attractive. TRIAL REGISTRATION: Smoking cessation in hospitalized smokers NCT01289275. Date of registration February 1, 2011; date of first patient August 3, 2011.
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Aconselhamento , Linhas Diretas , Pacientes Internados , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Projetos de Pesquisa , Abandono do Hábito de Fumar/métodos , Prevenção do Hábito de Fumar , Dispositivos para o Abandono do Uso de Tabaco , Administração Cutânea , Assistência ao Convalescente , California , Análise Custo-Benefício , Aconselhamento/economia , Custos de Medicamentos , Custos Hospitalares , Linhas Diretas/economia , Humanos , Nicotina/economia , Agonistas Nicotínicos/economia , Alta do Paciente , Recidiva , Fumar/economia , Fumar/psicologia , Abandono do Hábito de Fumar/economia , Telefone , Fatores de Tempo , Dispositivos para o Abandono do Uso de Tabaco/economia , Adesivo Transdérmico , Resultado do TratamentoRESUMO
OBJECTIVE: Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions, the only Food and Drug Administration-approved lipid formulation for clinical use. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Medical-surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital. PATIENTS: Adult medical-surgical intensive care unit patients. INTERVENTION: Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid emulsions. MEASUREMENTS: Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups. RESULTS: A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil-based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients received olive oil-based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6 [±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups. CONCLUSION: The administration of parenteral nutrition containing soybean oil-based and olive oil-based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults.
Assuntos
Emulsões Gordurosas Intravenosas/administração & dosagem , Nutrição Parenteral/métodos , Óleos de Plantas/administração & dosagem , Óleo de Soja/administração & dosagem , Adulto , Idoso , Cuidados Críticos , Método Duplo-Cego , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Azeite de Oliva , Estudos Prospectivos , Procedimentos Cirúrgicos Operatórios , Resultado do TratamentoAssuntos
Anti-Infecciosos/farmacocinética , Humor Aquoso/metabolismo , Compostos Aza/farmacocinética , Azepinas/farmacocinética , Extração de Catarata , Fluoroquinolonas/farmacocinética , Soluções Oftálmicas/farmacocinética , Quinolinas/farmacocinética , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Endoftalmite/prevenção & controle , Meia-Vida , Humanos , Testes de Sensibilidade Microbiana , MoxifloxacinaRESUMO
We report the engineering of the surface of the tobacco mosaic virus (TMV) virion with a mosquito decapeptide hormone, trypsin-modulating oostatic factor (TMOF). The TMV coat protein (CP) was fused to TMOF at the C terminus by using a read-through, leaky stop codon that facilitated expression of CP and chimeric CP-TMOF (20:1 ratio) that were coassembled into virus particles in infected Nicotiana tabacum. Plants that were infected with the hybrid TMV RNA accumulated TMOF to levels of 1.3% of total soluble protein. Infected tobacco leaf discs that were fed to Heliothis virescens fourth-instar larvae stunted their growth and inhibited trypsin and chymotrypsin activity in their midgut. Purified CP-TMOF virions fed to mosquito larvae stopped larval growth and caused death. Because TMV has a wide host range, expressing TMV-TMOF in plants can be used as a general method to protect them against agricultural insect pests and to control vector mosquitoes.
Assuntos
Aedes/efeitos dos fármacos , Aedes/crescimento & desenvolvimento , Inseticidas/administração & dosagem , Inseticidas/farmacologia , Oligopeptídeos/metabolismo , Vírus do Mosaico do Tabaco/metabolismo , Vírion/metabolismo , Ração Animal , Animais , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Genoma Viral/genética , Inseticidas/química , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Modelos Moleculares , Oligopeptídeos/química , Oligopeptídeos/genética , Doenças das Plantas/genética , Doenças das Plantas/virologia , Folhas de Planta/genética , Folhas de Planta/metabolismo , Folhas de Planta/virologia , Engenharia de Proteínas , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Nicotiana/genética , Nicotiana/metabolismo , Nicotiana/virologia , Vírus do Mosaico do Tabaco/química , Vírus do Mosaico do Tabaco/genética , Tripsina/metabolismo , Vírion/química , Vírion/genéticaRESUMO
RATIONALE: Although acute pulmonary embolism is epidemiologically associated with chronic thromboembolic pulmonary hypertension, the factors responsible for resistance to thrombolysis and a shift toward vascular remodeling within the pulmonary arteries of patients with chronic thromboembolic pulmonary hypertension are unknown. OBJECTIVE: Determine whether fibrin from patients is more resistant to plasmin-mediated lysis than fibrin from healthy control subjects. METHODS: Fibrinogen purified from patients and control subjects was used to prepare fibrin clots, which were subsequently digested with plasmin for various periods of time. The degradation of the alpha-, beta-, and gamma-chains of fibrin and the appearance of peptide fragments over time were assessed by polyacrylamide gel electrophoresis and Western blotting. MEASUREMENTS AND MAIN RESULTS: Densitometry of Coomassie-stained gels revealed significantly slower cleavage of all three polypeptide chains of fibrin from patients compared with control subjects (p < 0.05). In particular, release of N-terminal fragments from the beta-chain of fibrin, which promote cell signaling, cell migration, and angiogenesis, was retarded in patients compared with control subjects (p < 0.01). CONCLUSIONS: The relative resistance of patient fibrin to plasmin-mediated lysis may be due to alterations in fibrin(ogen) structure affecting accessibility to plasmin cleavage sites. The persistence of structural motifs of fibrin, such as the beta-chain N-terminus, within the pulmonary vasculature could promote the transition from acute thromboemboli into chronic obstructive vascular scars.