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1.
Nature ; 538(7625): 344-349, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27602946

RESUMO

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Azetidinas/uso terapêutico , Descoberta de Drogas , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Animais , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Azetidinas/farmacologia , Citosol/enzimologia , Modelos Animais de Doenças , Feminino , Fígado/efeitos dos fármacos , Fígado/parasitologia , Macaca mulatta/parasitologia , Malária Falciparum/prevenção & controle , Malária Falciparum/transmissão , Masculino , Camundongos , Fenilalanina-tRNA Ligase/antagonistas & inibidores , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Plasmodium falciparum/citologia , Plasmodium falciparum/enzimologia , Segurança
2.
Zhongguo Zhong Yao Za Zhi ; 45(22): 5459-5464, 2020 Nov.
Artigo em Zh | MEDLINE | ID: mdl-33350206

RESUMO

In order to screen the endophytic fungi that can enhance the host(Dendrobium catenatum) resistance to Sclerotium delphinii, the antagonism between each of the 43 endophytic fungi and the pathogen S. delphinii were tested. The results showed that 6 endophytic fungi(DCR2, DCR5, DCR21, DCR22, DCR42, DCR43) have strong activities against the pathogen, the inhibition rates were 49.2%, 49.2%, 47.2%, 56.2%, 53.2%, 48.0%, respectively. Then D. catenatum plantlets were inoculated with both S. delphinii and each of these six endophytic fungi. As a result, the incidence rates of leaves and stems of the D. catenatum plantlets inoculated with DCR2 and the pathogen were both significantly lower than those with other treatments, and the plantlet death rate was 0. It showed that DCR2 Trichoderma polysporum could effectively inhibit the southern blight disease of D. catenatum. Through the endophytic fungal re-isolation test, it was found that DCR2 can colonize in the roots, stems, and leaves of D. catenatum. The research will provide new ideas for the prevention and treatment of the southern blight disease of D. catenatum. It is also significant for reducing pesticide use, ensuring food safety, and promoting the sustainable development of D. catenatum industry. Furthermore, it will provide a basis for the disease control in other crops.


Assuntos
Dendrobium , Basidiomycota , Endófitos , Fungos , Hypocreales , Raízes de Plantas
3.
Med Sci Monit ; 24: 4869-4875, 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30006502

RESUMO

BACKGROUND The purpose of this study was to investigate whether DEX exerts protective mechanisms in rats with acute lung injury (ALI) induced by the endotoxin lipopolysaccharide (LPS). The mortality rate of ALI is extremely high. DEX, an a2 adrenergic receptor agonist, has potent anti-inflammatory and organ-protective effects in addition to its sedative and analgesic properties. We sought to elucidate whether DEX can attenuate acute lung injury. MATERIAL AND METHODS Forty-eight Wister rats were randomly divided into 4 groups (n=12, per group): the normal saline control (NS) group, receiving tail-vein injection of 0.9% normal saline (5 mL/kg); the LPS (L) group, receiving tail-vein injection of LPS (8 mg/kg); the LPS+DEX (L+D) group, receiving tail-vein injection of LPS (8 mg/kg), 0.5h before treated with DEX (50 ug/kg); and the DEX+LPS (D+L) group, receiving tail-vein injection of LPS (8 mg/kg) 0.5 h after being treated with DEX (50 ug/kg). Then, we measured the wet­to­dry weight ratio of lung tissue, the ALI pathology score, and HE staining of lung tissue, and assessed the Oxygen Tension index. RESULTS The present study revealed that LPS­induced rats exhibited significant lung injury, characterized by the deterioration of histopathology, ALI Pathology Score, wet­to­dry weight ratio, and Oxygen Tension index (MBP, PaO2, PaCO2, PH, HCO3-, and Lac), which were attenuated by DEX treatment. CONCLUSIONS Collectively, the present results demonstrate elucidate the molecular mechanisms by which DEX ameliorates LPS­induced ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Dexmedetomidina/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Endotoxinas , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Masculino , Ratos , Ratos Sprague-Dawley
4.
Herz ; 42(6): 573-584, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27830272

RESUMO

BACKGROUND: Once hypertension is established, increased mechanical stretch stress becomes a leading cause of vascular remodeling. Clinical antihypertension guidelines demonstrate that antihypertension drugs prevent vascular remodeling in hypertensive patients mainly by lowering blood pressure, suggesting an indirect way of reducing the effects of stretch stress (hypertension). Whether these drugs can directly block the effects of the stretch stress on vascular remodeling has not been reported to date. This study was designed to answer this question and explore the underlying mechanisms. METHODS: Cultured quiescent vascular smooth muscle cells (VSMCs) were stimulated by stretch stress after pretreatment with nifedipine and hydrochlorothiazide. The phosphorylation levels of extracellular signal-regulated kinases (ERKs), c­Jun NH2-terminal protein kinases (JNKs), and p38 mitogen-activated protein kinase (MAPK) in VSMCs were detected via Western blotting. The treated cells were stained using triple-labeled immunofluorescence with Ki67 antibody and a TUNEL kit in the presence of DAPI for the detection of proliferative, apoptotic, and resting cells. RESULTS: Compared with the negative control, both nifedipine and hydrochlorothiazide had no influence on the phosphorylation of MAPKs and on the proliferation and apoptosis of VSMCs in resting state. Stretch stress could significantly induce increased phosphorylation of MAPKs as well as proliferation and apoptosis of VSMCs. Nifedipine inhibited the effects of stretch stress in a dose-dependent manner. Contrary to the effects of nifedipine, hydrochlorothiazide synergistically amplified the effects induced by stretch stress. CONCLUSION: Nifedipine and hydrochlorothiazide have opposing functions in the increased phosphorylation of MAPK and in the proliferation and apoptosis of VSMCs induced by stretch stress. The former plays a role as an inhibitor, while the latter functions as a promoter.


Assuntos
Apoptose/efeitos dos fármacos , Hidroclorotiazida/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Músculo Liso Vascular/efeitos dos fármacos , Nifedipino/farmacologia , Remodelação Vascular/efeitos dos fármacos , Apoptose/fisiologia , Western Blotting , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Imunofluorescência , Marcação In Situ das Extremidades Cortadas , Técnicas In Vitro , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/fisiopatologia , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Anesthesiology ; 123(2): 307-19, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26083768

RESUMO

BACKGROUND: Although deviations in intraoperative blood pressure are assumed to be associated with postoperative mortality, critical blood pressure thresholds remain undefined. Therefore, the authors estimated the intraoperative thresholds of systolic blood pressure (SBP), mean blood pressure (MAP), and diastolic blood pressure (DBP) associated with increased risk-adjusted 30-day mortality. METHODS: This retrospective cohort study combined intraoperative blood pressure data from six Veterans Affairs medical centers with 30-day outcomes to determine the risk-adjusted associations between intraoperative blood pressure and 30-day mortality. Deviations in blood pressure were assessed using three methods: (1) population thresholds (individual patient sum of area under threshold [AUT] or area over threshold 2 SDs from the mean of the population intraoperative blood pressure values), (2). absolute thresholds, and (3) percent change from baseline blood pressure. RESULTS: Thirty-day mortality was associated with (1) population threshold: systolic AUT (odds ratio, 3.3; 95% CI, 2.2 to 4.8), mean AUT (2.8; 1.9 to 4.3), and diastolic AUT (2.4; 1.6 to 3.8). Approximate conversions of AUT into its separate components of pressure and time were SBP < 67 mmHg for more than 8.2 min, MAP < 49 mmHg for more than 3.9 min, DBP < 33 mmHg for more than 4.4 min. (2) Absolute threshold: SBP < 70 mmHg for more than or equal to 5 min (odds ratio, 2.9; 95% CI, 1.7 to 4.9), MAP < 49 mmHg for more than or equal to 5 min (2.4; 1.3 to 4.6), and DBP < 30 mmHg for more than or equal to 5 min (3.2; 1.8 to 5.5). (3) Percent change: MAP decreases to more than 50% from baseline for more than or equal to 5 min (2.7; 1.5 to 5.0). Intraoperative hypertension was not associated with 30-day mortality with any of these techniques. CONCLUSION: Intraoperative hypotension, but not hypertension, is associated with increased 30-day operative mortality.


Assuntos
Hospitais de Veteranos/tendências , Hipertensão/mortalidade , Hipotensão/mortalidade , Monitorização Intraoperatória/mortalidade , Monitorização Intraoperatória/tendências , Complicações Pós-Operatórias/mortalidade , Determinação da Pressão Arterial/mortalidade , Determinação da Pressão Arterial/tendências , Estudos de Coortes , Feminino , Humanos , Hipertensão/diagnóstico , Hipotensão/diagnóstico , Masculino , Mortalidade/tendências , Complicações Pós-Operatórias/diagnóstico , Estudos Retrospectivos , Fatores de Tempo
6.
Br J Cancer ; 110(2): 530-4, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24292448

RESUMO

BACKGROUND: The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes. METHODS: We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person-years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries. RESULTS: Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54-1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30-1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77-7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33-1.00) for women aged 50 years and above. CONCLUSION: The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa , Canadá/epidemiologia , Neoplasias Colorretais/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Incidência , Pessoa de Meia-Idade , Risco , Estados Unidos/epidemiologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-25137537

RESUMO

This study aimed to isolate and characterize a new arsenic (As)-tolerant bacterial strain (XJ-1) from the Halosol soil, to evaluate its As tolerance, and to examine the variation in composition and relative content of accumulated photosynthetic pigments in response to As. The experiments were performed with high-performance liquid chromatography (HPLC), inductively-coupled plasma mass spectrometry (ICP-MS), liquid chromatography/mass spectrometry (LC/MS), thin-layer chromatography (TLC) and grayscale intensity image analysis using Gel-Pro analyzer software. Strain XJ-1 was identified as Rhodobacter (R.) capsulatus based on 16S rRNA gene sequencing and physiological characteristics. Strain XJ-1 was able to grow when exposed to arsenite [As(III)] and arsenate [As(V)] under anaerobic-light conditions. The median effective concentrations (EC50) of As(III) and As(V) were 0.61 mM and 2.03 mM, respectively. Strain XJ-1 could reduce As(V) to As(III), but As(III) could not be transformed back to As(V) or other organic As compounds. Accumulation of bacteriochlorophylls and carotenoids in strain XJ-1 varied in the presence of 0.2-1.2 mM As(III) and 0-2.5 mM As(V). As exposure resulted in pronounced variation in compositions and contents of photosynthetic pigments, especially hydroxyspheroidene, bacteriophaeophytin, the ratio of tetrahydrogeranylgeranyl to phytylated BChl a, and the ratio of spheroidene to spheroidenone. This research highlights the adaptative response of R. capsulatus strain XJ-1 photosystems to environmental As, and demonstrates the potential of utilizing the sensitivity of its photosynthetic pigments to As(III) and As(V) for the biodetection of As in the environment.


Assuntos
Arseniatos/toxicidade , Arsenitos/toxicidade , Carotenoides/metabolismo , Clorofila/metabolismo , Rhodobacter capsulatus/efeitos dos fármacos , Arsênio/toxicidade , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Espectrometria de Massas/métodos , Fotossíntese/fisiologia , RNA Ribossômico 16S/genética , Rhodobacter capsulatus/genética , Rhodobacter capsulatus/crescimento & desenvolvimento , Rhodobacter capsulatus/metabolismo
8.
Br J Cancer ; 107(12): 2005-9, 2012 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-23099806

RESUMO

BACKGROUND: Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation. METHODS: We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases. RESULTS: Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03-5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36-7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family. CONCLUSION: The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Heterozigoto , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade
9.
Anesth Analg ; 113(3): 550-6, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21596879

RESUMO

BACKGROUND: Current drugs for induction and maintenance of sedation in mechanically ventilated patients in the intensive care unit have limitations. Fospropofol, a prodrug of propofol, has not been studied as a sedative in the ICU setting. METHODS: In this randomized, open-label pilot study, patients received 1 of 3 regimens with a goal of maintaining a Ramsay Sedation Score of 2 to 5: (1) fospropofol IV infusion with a bolus and increased infusion rate for agitation events (infusion/bolus); (2) fospropofol IV infusion with an increased infusion rate for agitation events (infusion only); or (3) propofol IV infusion with an increased infusion rate for agitation events. RESULTS: Sixty patients received study drug and were included in the safety and efficacy analyses. Because incidence rates for adverse events were similar between fospropofol groups, and because the study was not powered to determine significant differences between treatment groups for safety variables, adverse events for both fospropofol groups were combined. In the fospropofol groups, 28 out of 38 patients (74%) experienced treatment-emergent adverse events in comparison with 14 out of 22 patients (64%) in the propofol group. The most common treatment-emergent adverse events with fospropofol were procedural pain (21.1%) and nausea (13.2%). Two patients (1 each in the fospropofol infusion/bolus and the propofol groups) experienced hypotension during the study as a potential sedation-related adverse event. Mean plasma formate levels were not significantly different among groups. Patients in all 3 treatment groups maintained Ramsay Sedation Scores of 2 to 5 for >90% of the time they were sedated. CONCLUSION: This pilot study suggests that fospropofol, administered in either an infusion/bolus or infusion-only regimen, is tolerable and effective for short-term induction and maintenance of sedation in mechanically ventilated intensive care unit patients.


Assuntos
Cuidados Críticos , Hipnóticos e Sedativos/administração & dosagem , Intubação Intratraqueal , Propofol/análogos & derivados , Respiração Artificial , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Infusões Intravenosas , Injeções Intravenosas , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Propofol/administração & dosagem , Propofol/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
10.
J Agric Food Chem ; 69(48): 14387-14401, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34843230

RESUMO

Saponins, prominent secondary plant metabolites, are recognized for their roles in plant defense and medicinal benefits. Soyasaponins, commonly derived from legumes, are a class of triterpenoid saponins that demonstrate significant potential for plant and human health applications. Previous research and reviews largely emphasize human health effects of soyasaponins. However, the biological effects of soyasaponins and their implications for plants in the context of human health have not been well-discussed. This review provides comprehensive discussions on the biological roles of soyasaponins in plant defense and rhizosphere microbial interactions; biosynthetic regulation and compound production; immunological effects and potential for therapeutics; and soyasaponin acquisition attributed to processing effects, bioavailability, and biotransformation processes based on recent soyasaponin research. Given the multifaceted biological effects elicited by soyasaponins, further research warrants an integrated approach to understand molecular mechanisms of regulations in their production as well as their applications in plant and human health.


Assuntos
Fabaceae , Ácido Oleanólico , Saponinas , Disponibilidade Biológica , Humanos , Glycine max
11.
J Clin Invest ; 91(6): 2429-36, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8514855

RESUMO

To assess the effect of hemodialysis on protein metabolism, leucine flux was measured in seven patients before, during, and after high efficiency hemodialysis using cuprophane dialyzers and bicarbonate dialysate during a primed-constant infusion of L-[1-13C]leucine. The kinetics [mumol/kg per h, mean +/- SD] are as follows: leucine appearance into the plasma leucine pool was 86 +/- 28, 80 +/- 28, and 85 +/- 25, respectively, before, during, and after dialysis. Leucine appearance into the whole body leucine pool, derived from plasma [1-13C]alpha-ketoisocaproate enrichment, was 118 +/- 31, 118 +/- 31, and 114 +/- 28 before, during, and after dialysis, respectively. In the absence of leucine intake, appearance rate reflects protein degradation, which was clearly unaffected by dialysis. Leucine oxidation rate was 17.3 +/- 7.8 before, decreased to 13.8 +/- 7.8 during, and increased to 18.9 +/- 10.3 after dialysis (P = 0.027). Leucine protein incorporation was 101 +/- 26 before, was reduced to 89 +/- 23 during, and returned to 95 +/- 23 after dialysis (P = 0.13). Leucine net balance, the difference between leucine protein incorporation and leucine release from endogenous degradation, was -17.3 +/- 7.8 before, decreased to -28.5 +/- 11.0 during, and returned to -18.9 +/- 10.3 after dialysis (P < 0.0001). This markedly more negative leucine balance during dialysis was accountable by dialysate leucine loss, which was 14.4 +/- 6.2 mumol/kg per h. These data suggest that hemodialysis using a cuprophane membrane did not acutely induce protein degradation. It was, nevertheless, a net catabolic event because protein synthesis was reduced and amino acid was lost into the dialysate.


Assuntos
Leucina/metabolismo , Proteínas/metabolismo , Diálise Renal , Adulto , Bicarbonatos/metabolismo , Dióxido de Carbono/metabolismo , Isótopos de Carbono , Feminino , Humanos , Cetoácidos/metabolismo , Cinética , Leucina/sangue , Masculino , Pessoa de Meia-Idade
12.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 29(4): 397-401, 2017 Aug 14.
Artigo em Zh | MEDLINE | ID: mdl-29508567

RESUMO

China's prevention and control of parasitic diseases has made remarkable achievements. However, the prevalence and transmission of parasitic diseases is impacted by the complicated natural and social factors of environment, natural disasters, population movements, and so on. Therefore, there are still the risks of the outbreak of emergency parasitic diseases affairs, which may affect the control effectiveness of parasitic diseases and endanger the social stability seriously. In this article, we aim at the analysis of typical cases of emergency parasitic disease affairs and their impacts on public health security in China in recently years, and we also elaborate the disposal characteristics of emergency parasitic disease affairs, and propose the establishment of response system to emergency parasitic disease affairs in China, including the organizational structure and response flow path, and in addition, point out that, in the future, we should strengthen the system construction and measures of the response system to emergency parasitic disease affairs, so as to control the risk and harm of parasitic disease spread as much as possible and to realize the early intervention and proper disposal of emergency parasitic disease affairs.


Assuntos
Surtos de Doenças , Doenças Parasitárias/prevenção & controle , Saúde Pública , China , Desastres , Humanos
13.
Int J Radiat Oncol Biol Phys ; 65(3): 726-32, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16626888

RESUMO

PURPOSE: To assess the need for gross tumor volume (GTV) delineation protocols in head-and-neck cancer (HNC) treatment planning by use of positron emission tomography (PET)/computed tomography (CT) fusion imaging. Assessment will consist of interobserver and intermodality variation analysis. METHODS AND MATERIALS: Sixteen HNC patients were accrued for the study. Four physicians (2 neuroradiologists and 2 radiation oncologists) contoured GTV on 16 patients. Physicians were asked to contour GTV on the basis of the CT alone, and then on PET/CT fusion. Statistical analysis included analysis of variance for interobserver variability and Student's paired sample t test for intermodality and interdisciplinary variability. A Boolean pairwise analysis was included to measure degree of overlap. RESULTS: Near-significant variation occurred across physicians' CT volumes (p = 0.09) and significant variation occurred across physicians' PET/CT volumes (p = 0.0002). The Boolean comparison correlates with statistical findings. One radiation oncologist's PET/CT fusion volumes were significantly larger than his CT volumes (p < 0.01). Conversely, the other radiation oncologist's CT volumes tended to be larger than his fusion volumes (p = 0.06). No significant interdisciplinary variation was seen. Significant disagreement occurred between radiation oncologists. CONCLUSION: Significant differences in GTV delineation were found between multiple observers contouring on PET/CT fusion. The need for delineation protocol has been confirmed.


Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Compostos Radiofarmacêuticos
14.
J Am Acad Dermatol ; 54(6): 992-1002, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16713453

RESUMO

BACKGROUND: Identification of critical autoantigenic T-cell epitopes is key to developing antigen-based therapies for autoimmune diseases, including psoriasis. Our previous work demonstrated that 3 peptides on keratin 17 are able to stimulate peripheral blood lymphocytes of HLA-DRB1*07-positive patients with psoriasis and to serve as immunodominant T-cell epitopes. OBJECTIVE: We sought to determine antagonistic altered peptide ligands to psoriatic T cells with a down-modulatory effect in inhibiting keratinocyte proliferation. METHODS: Psoriatic altered peptide ligands were generated by single alanine residue substitutions at a critical T-cell receptor contact residue position. Antagonistic altered peptide ligands were identified by suppression screening of psoriatic T-cell activation and keratinocyte proliferation. RESULTS: Altered peptide ligands 119R and 355L can inhibit psoriatic T-cell activation more effectively than other altered peptide ligands, especially 355L, with inhibition of T-cell proliferation and the secretion of interferon gamma and interleukin 2 in parallel with the up-regulation of interleukins 4 and 10 as well as transforming growth factor-beta. In coincubation assay, altered peptide ligands 119R and 355L can down-regulate the function of psoriatic T cells more effectively than wild-type epitopes solely, but less effectively than altered peptide ligands solely. In prepulse assay altered peptide ligand 119R can down-regulate the activation of psoriatic T cells more effectively than in coincubation but less effectively as compared with altered peptide ligand 119R only. Altered peptide ligand 355L was also shown to have a similar presentation. T-cell culture supernatants (1:100) from the concentrations (10 microg.mL(-1) and 100 microg.mL(-1) with 119R, 100 microg.mL(-1) with 355L) were more effective than the other ratios in inhibiting keratinocyte proliferation. LIMITATIONS: This study had a relatively small sample size (52 patients and 48 healthy controls). CONCLUSION: Our findings show that the altered peptide ligands 119R (VAALEEANTELEVKI) and 355L (ENRYCVQASQIQGLI) are capable of inhibiting proliferative responses of psoriatic T cells and keratinocyte proliferation in vitro, at least, with enhanced helper T cell type 2 polarization. Thus, to our knowledge, this article is the first report of the demonstration of therapeutic activity of altered peptide ligands derived from keratin 17.


Assuntos
Queratinócitos/citologia , Queratinas/fisiologia , Psoríase/patologia , Linfócitos T/citologia , Proliferação de Células , Células Cultivadas , Humanos , Ligantes , Peptídeos , Receptores de Antígenos de Linfócitos T/fisiologia
15.
Neuroscience ; 124(2): 341-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14980384

RESUMO

Central administration of angiotensin IV (Ang IV) or its analogues enhance performance of rats in passive avoidance and spatial memory paradigms. The purpose of this study was to examine the effect of a single bolus injection of two distinct AT4 ligands, Nle1-Ang IV or LVV-haemorphin-7, on spatial learning in the Barnes circular maze. Mean number of days for rats treated with either Nle1-Ang IV or LVV-haemorphin-7 to achieve learner criterion is significantly reduced compared with controls (P < 0.001 and P < 0.05 respectively). This is due to enhanced ability of the peptide-treated rats to adopt a spatial strategy for finding the escape hatch. In all three measures of learning performance, (1) the number of errors made, (2) the distance travelled and (3) the latency in finding the escape hatch, rats treated with either 100 pmol or 1 nmol of Nle1-Ang IV or 100 pmol LVV-haemorphin-7 performed significantly better than the control groups. As early as the first day of testing, the rats treated with the lower dose of Nle1-Ang IV or LVV-haemorphin-7 made fewer errors (P < 0.01 and P < 0.05 respectively) and travelled shorter distances (P < 0.05 for both groups) than the control animals. The enhanced spatial learning induced by Nle1-Ang IV (100 pmol) was attenuated by the co-administration of the AT4 receptor antagonist, divalinal-Ang IV (10 nmol). Thus, administration of AT4 ligands results in an immediate potentiation of learning, which may be associated with facilitation of synaptic transmission and/or enhancement of acetylcholine release.


Assuntos
Angiotensina II/análogos & derivados , Antagonistas de Receptores de Angiotensina , Hemoglobinas/farmacologia , Aprendizagem/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Comportamento Espacial/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal , Injeções Intraventriculares/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores de Angiotensina , Fatores de Tempo
16.
J Biochem Biophys Methods ; 45(2): 231-9, 2000 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-10989139

RESUMO

The microcalorimetric bioassay for acute cellular toxicity is based on metabolic heat production from cultured cells. Microcalorimetry is a quantitative, inexpensive, and versatile method for toxicology research. The biological response to toxicants is the inhibition of the heat production rate in cells and toxicity is expressed as the concentration of toxicant that is 50% effective in this inhibition (IC(50)). In this paper, the effect of Cd(2+) on Rhizopus nigricans growth was investigated at 25 degrees C. The relationship between growth rate constants (k) and concentration of Cd(2+) (C) shows a logarithmic normal distribution, and described as k=1. 2742x10(61)exp[-1.810x10(-3)(C+283.0)(2)], and IC(50) is 0.72 microg/ml. These signals are readily obtained by an LKB 2277-204 heat conduction microcalorimeter.


Assuntos
Cádmio/toxicidade , Calorimetria/métodos , Rhizopus/efeitos dos fármacos , Calorimetria/instrumentação , Cinética , Rhizopus/crescimento & desenvolvimento , Rhizopus/metabolismo , Termogênese/efeitos dos fármacos
17.
J Biochem Biophys Methods ; 46(1-2): 1-9, 2000 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-11086189

RESUMO

A microcalorimetric technique based on the bacterial heat-output was explored to evaluate the stimulatory effect of La(3+) on Escherichia coli. The power-time curves of the growth metabolism of E. coli and the effect of La(3+) on it were studied using an LKB-2277 BioActivity Monitor, stopped-flow method, at 37 degrees C. For evaluation of the results, the maximum power (P(max)), the growth rate constants (k) and the heat effects (Q(LOG), Q(STAT)) for the log phase, the stationary phase and the total heat effect (Q(T)) for E. coli were determined. The microcalorimetric method agreed with the conventional methods, such as cell numbers and biomass. La(3+) in the concentration ranges of 0-400 microg/ml has stimulatory effects on E. coli, while La(3+) ion of higher concentrations (>400 microg/ml) can inhibit the growth. This phenomenon is very similar to those observed from the in vitro cells and tissues from animals, plants and some microorganisms by other methods.


Assuntos
Calorimetria/métodos , Escherichia coli/efeitos dos fármacos , Lantânio/farmacologia , Biomassa , Calorimetria/instrumentação , Cátions/farmacologia , Divisão Celular/efeitos dos fármacos , Contagem de Colônia Microbiana , Relação Dose-Resposta a Droga , Escherichia coli/citologia , Escherichia coli/metabolismo , Temperatura Alta , Cinética
18.
J Endourol ; 10(4): 319-23, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8872727

RESUMO

The primary goal of this study was to evaluate differences in carbon dioxide metabolism between patients undergoing transperitoneal or extraperitoneal laparoscopic pelvic lymph node dissection (L-PLND) for staging of adenocarcinoma of the prostate (CaP). Eighteen candidates undergoing L-PLND were divided between the transperitoneal (N = 12) and extraperitoneal (N = 6) approaches. End-tidal partial pressure of CO2 (PeCO2) and minute volume of expired CO2 (VCO2) were considered indicators of CO2 absorption. These two parameters were monitored intraoperatively utilizing a metabolic cart and Ohmeda Rascal-II. The cardiostimulatory effect of increasing serum CO2 and the ventilatory countermeasures used to correct the iatrogenic hypercapnia associated with CO2 insufflation were also measured. With the exception of the region of CO2 insufflation, the operative procedure and perioperative care were identical for the two groups. Preoperative patient characteristics were similar. The mean time of CO2 insufflation was 136 minutes for the transperitoneal group and 120 minutes for the extraperitoneal group. The absorption of CO2 was significantly greater and more rapid during extraperitoneal L-PLND. This may be attributable to more profound CO2 absorption from the parietal peritoneal surface compounded by subcutaneous CO2 emphysema. Disruption of microvascular and lymphatic channels during the development of the extraperitoneal working space facilitates direct CO2 absorption into the intravascular space. A minor increase in heart rate and systolic blood pressure was noted during CO2 insufflation. In all but one patient (extraperitoneal group), hypercarbia and acidemia were prevented by an increased ventilatory rate. The potential dysrhythmogenicity of hypercarbia may contraindicate the extraperitoneal approach in patients with cardiopulmonary disease.


Assuntos
Dióxido de Carbono/metabolismo , Sistemas Computacionais , Laparoscopia/métodos , Excisão de Linfonodo/métodos , Monitorização Intraoperatória , Pelve/cirurgia , Adenocarcinoma/patologia , Idoso , Homeostase , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Estadiamento de Neoplasias , Peritônio , Neoplasias da Próstata/patologia , Espaço Retroperitoneal
19.
Sci Total Environ ; 128(2-3): 151-6, 1993 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-8424157

RESUMO

In this study, significant correlations were discovered between the following three parameters: (i) pH values of human hair, (ii) K, Ca, Mg, Zn contents of human hair and (iii) sex. We also discovered that most trace elements are not significantly correlated with hair pH.


Assuntos
Cálcio/análise , Cabelo/química , Magnésio/análise , Potássio/análise , Zinco/análise , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Fatores Sexuais
20.
Chemosphere ; 40(8): 845-9, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10718577

RESUMO

The heat output of the non-growth metabolism of Chlorella vulgaris has been determined using an LKB-2277 BioActivity Monitor. The experimental results indicate that there is a turn-point on the metabolic thermogenic curves, which can be divided into two parts, an early phase and a later phase. For the early phase, there is a linear relationship between the metabolic power (P) and the cell concentration (C), and that the heat output produced by a single cell's metabolism (P0) depends on the cell concentration (C) and is inhibited by the cell density, the thermokinetic equation of their metabolism is dP/dt = k0, k0 = 0.


Assuntos
Chlorella/fisiologia , Metabolismo Energético , Calorimetria Indireta , Temperatura Alta , Modelos Teóricos
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