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1.
Health Sci Rep ; 6(5): e1295, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37251521

RESUMO

Despite the successes achieved so far with the Global Programme to Eliminate Lymphatic Filariasis, there is still an appreciable number of lymphatic filarial patients who need alternative treatment and morbidity management strategies. The unresponsiveness of some cohorts to the drugs used in the mass drug administration program is currently raising a lot of questions and this needs urgent attention. Natural medicinal plants have a long-standing history of being effective against most disease conditions. Countries such as India have been able to integrate their natural plant remedies into the treatment of lymphatic filarial conditions, and the results are overwhelmingly positive. Components of Azadirachta indica A. Juss, Parkia biglobosa, Adansonia digitata, and Ocimum spp have been shown to have anti-inflammatory, anticancerous, and antimicrobial activities in animal models. Therefore, this review calls for attention toward the use of natural plant components as an alternate treatment against lymphatic filariasis to help reduce the World Health Organization's burden of providing drugs for people in need of treatment every year.

2.
Chemistry ; 24(67): 17677-17680, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30207403

RESUMO

We have screened small molecule libraries specifically for inhibitors that target WWP2, an E3 ubiquitin ligase associated with tumour outgrowth and spread. Selected hits demonstrated dose-dependent WWP2 inhibition, low micromolar IC50 values, and inhibition of PTEN substrate-specific ubiquitination. Binding to WWP2 was confirmed by ligand-based NMR spectroscopy. Furthermore, we used a combination of STD NMR, the recently developed DEEP-STD NMR approach, and docking calculations, to propose for the first time an NMR-validated 3D molecular model of a WWP2-inhibitor complex. These first generation WWP2 inhibitors provide a molecular framework for informing organic synthetic approaches to improve activity and selectivity.


Assuntos
Inibidores Enzimáticos/química , Bibliotecas de Moléculas Pequenas/química , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Sítios de Ligação , Descoberta de Drogas , Inibidores Enzimáticos/metabolismo , Humanos , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Ressonância Magnética Nuclear Biomolecular , PTEN Fosfo-Hidrolase/metabolismo , Estrutura Terciária de Proteína , Bibliotecas de Moléculas Pequenas/metabolismo , Solubilidade , Ubiquitina-Proteína Ligases/metabolismo
3.
Cytokine ; 102: 131-140, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28807497

RESUMO

Early acting cytokines and growth factors such as those of the CD131 ßc subunit, may offer an alternative method to the current use of antibiotics and chemicals such as anthelmintics in maintaining Porcine (Po) health. Thus far, the recombinant Po (rPo) Granulocyte-macrophage colony-stimulating factor (GM-CSF), rPo interleukin-3 (IL-3) and rPo interleukin-5 (IL-5) proteins have been identified and cloned and the biological activity of each cytokine has been confirmed in vitro, however, in vivo immune system regulation and hematopoietic stem cell (HSC) augmentation are regulated by numerous cytokines and cellular signals within the bone marrow (BM) niche. In order to quantify the use of recombinant cytokines in augmenting the immune response, it is necessary to determine the stages of hematopoiesis induced by each cytokine and possible areas of synergy requiring further investigation. Here we used the chemotherapeutic agent 5-fluorouracil (5-FU), to chemically induce a state of myelosuppression in young pigs. This allowed for the monitoring of both the autologous BM reconstitution and recombinant cytokine induced BM repopulation, precursor cell proliferation and cellular differentiation. The recombinant cytokines PoGM-CSF, PoIL-3 and PoIL-5 were administered by intramuscular injections (i.m.) following confirmation of 5-FU induced leukocytopenia. Blood and BM samples were collected and then analysed for cell composition. Statistically significant results were observed in several blood cell populations including eosinophils for animals treated with rPoIL-5, rPoGM-CSF and basophils for animals treated with rPoIL-3. BM analysis of CD90+ and CD172a+ cells confirmed myelosuppression in week one with significant results observed between rPoIL-3 and the 5-FU control group in week two and for the rPoGM-CSF group in week three. These results have demonstrated the effects of each of these rPo cytokines within the hematopoietic processes of the pig and may demonstrate similar outcomes in other mammalian models including human.


Assuntos
Subunidade beta Comum dos Receptores de Citocinas/metabolismo , Citocinas/imunologia , Sus scrofa/imunologia , Animais , Antígenos CD/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Subunidade beta Comum dos Receptores de Citocinas/química , Citocinas/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hematopoese/efeitos dos fármacos , Hematopoese/imunologia , Imunização/métodos , Imunização/veterinária , Interleucina-3/imunologia , Interleucina-3/farmacologia , Interleucina-5/imunologia , Interleucina-5/farmacologia , Subunidades Proteicas , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Antígenos Thy-1/metabolismo
4.
Intern Med J ; 46(6): 694-702, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27009846

RESUMO

BACKGROUND: Greater numbers of persons aged over 80 years are admitted to intensive care units (ICU) compared with 15 years ago. Outcomes other than death such as physical dependence and cognitive impairment and treatment burden are important to older people. AIMS: The aims of this study were to determine the long-term outcomes of functional impairment, health-related quality of life (HRQoL) and the self-reported burden of treatment in a sample of patients aged 80 years and above admitted to ICU. Half of the cohort were admitted for elective cardiac surgery, the rest for non-cardiac surgery and medical conditions. METHODS: In this longitudinal cohort study, in a tertiary level ICU, we measured HRQoL using the SF-36 and functional status using the modified Barthel Index at several time points over a 2-year follow-up period. We also assessed treatment burden by asking participants whether they thought the episode of care was worthwhile. RESULTS: A total of 348 patients was recruited into the study. One-fifth of the cohort had died by the 2-year follow-up data collection point. There was an improvement in physical functioning in the cardiac surgery group at 6 months which was not sustained. There was no change in HRQoL at 2 years in either group. The majority valued the episode of care. CONCLUSION: We demonstrated that HRQoL and previous lifestyle is preserved in the majority following ICU admission, associated with a high level of patient valuation of the episode of care.


Assuntos
Doença Crônica/mortalidade , Efeitos Psicossociais da Doença , Cuidados Críticos/normas , Nível de Saúde , Qualidade de Vida , Idoso de 80 Anos ou mais , Austrália , Comorbidade , Feminino , Hospitais Privados , Humanos , Unidades de Terapia Intensiva , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Avaliação de Resultados da Assistência ao Paciente , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários
5.
Clin Cancer Res ; 16(1): 279-90, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20028752

RESUMO

PURPOSE: Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti-epidermal growth factor receptor monoclonal antibody panitumumab in advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line). RESULTS: Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively. CONCLUSIONS: Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Carboplatina/administração & dosagem , Feminino , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Niacinamida/uso terapêutico , Oligonucleotídeos , Paclitaxel/administração & dosagem , Panitumumabe
6.
Acta Crystallogr C ; 64(Pt 1): o7-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18216456

RESUMO

The title compound, C14H18INO, crystallizes as +sc/+sp/+sc 2-iodoanilide molecules (and racemic opposites) and shows significant intermolecular I...O interactions in the solid state, forming dimeric pairs about centres of symmetry. Under asymmetric Heck conditions, the S enantiomer of the dihydroindol-2-one was obtained using (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(R)-BINAP], suggesting a mechanism that proceeds by oxidative addition to give the title (P) enantiomer of the compound and pro-S coordination of the Re face of the alkene in a conformation similar to that defined crystallographically, except that rotation about the C-C bond of the butenyl group is required.


Assuntos
Anilidas/química , Hidrocarbonetos Iodados/química , Isomerismo , Estrutura Molecular
7.
Liver Transpl ; 11(10): 1282-4, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16184556

RESUMO

Appendicitis among liver transplant recipients has not been described in the current literature. We report 8 recipients who experienced appendicitis three weeks to 181 months after liver transplantation (LT). Initial presenting findings differed from the nonimmunosuppressed population in that a majority of the patients did not have leukocytosis (>10,000 cells/mm3). Four patients experienced perforation, three of whom presented three days after the development of abdominal pain. All patients recovered after surgery without untoward sequela.


Assuntos
Apendicite/epidemiologia , Transplante de Fígado , Complicações Pós-Operatórias/epidemiologia , Dor Abdominal , Antibacterianos/uso terapêutico , Apendicectomia , Apendicite/complicações , Apendicite/cirurgia , Seguimentos , Humanos , Perfuração Intestinal/etiologia , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Fatores de Tempo
8.
Obes Rev ; 5(3): 153-65, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15245384

RESUMO

The adipocytokines are biologically active polypeptides that are produced either exclusively or substantially by the adipocytes, and act by endocrine, paracrine, and autocrine mechanisms. Most have been associated with obesity, hyperinsulinaemia, type 2 diabetes, and chronic vascular disease; in addition, six adipocytokines--vascular endothelial growth factor, hepatocyte growth factor, leptin, tumour necrosis factor-alpha, heparin-binding epidermal growth factor-like growth factor, and interleukin-6--promote angiogenesis while one, adiponectin, is inhibitory. Obesity and insulin resistance have both been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis. Angiogenesis is essential for breast cancer development and progression, and so it is plausible that obesity-related increases in adipocytokine production and a reduction in adiponectin may adversely affect breast cancer outcome by their angiogenesis-related activities. There is also experimental evidence that some adipocytokines can act directly on breast cancer cells to stimulate their proliferation and invasive capacity. Thus, adipocytokines may provide a biological mechanism by which obesity and insulin resistance are causally associated with breast cancer risk and poor prognosis. Both experimental and clinical studies are needed to develop this concept, and particularly in oestrogen-independent breast cancers where preventive and therapeutic options are limited.


Assuntos
Adipócitos/metabolismo , Neoplasias da Mama/etiologia , Citocinas/fisiologia , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intercelular , Obesidade/complicações , Adiponectina , Animais , Composição Corporal/fisiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Insulina/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Prognóstico , Proteínas/metabolismo , Fatores de Risco
9.
Br J Oral Maxillofac Surg ; 42(2): 155-7, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15013549

RESUMO

Swellings on the head are common, but all require appropriate investigation and caution must be exercised during surgical intervention. We report a patient in whom an attempt at biopsy of a swelling in the scalp was made without any radiological imaging and led to an intracranial complication that caused a neurological deficit. The lesion was an intradiploic epidermal cyst. Though appropriate precautions are usually taken, lessons previously learnt are sometimes forgotten. We would therefore like to remind readers that swellings of the scalp that seem to be attached to the skull on clinical examination should be investigated by radiographs and preferably by computed tomography before surgical intervention because of the possibility of intracranial extension.


Assuntos
Biópsia por Agulha/efeitos adversos , Cisto Epidérmico/patologia , Hematoma Epidural Craniano/etiologia , Doença Iatrogênica , Osso Temporal/patologia , Adulto , Doenças Ósseas/patologia , Paralisia Facial/etiologia , Feminino , Hematoma Epidural Craniano/diagnóstico por imagem , Humanos , Radiografia
10.
Transplantation ; 72(4): 666-70, 2001 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-11544428

RESUMO

BACKGROUND: Malnutrition is a common complication of end-stage liver disease. It is frequently not a priority of treatment before liver transplantation. The purpose of this study was to examine whether prospective preoperative nutritional assessment could predict resource utilization and outcome after liver transplantation. METHODS: We retrospectively reviewed 109 sequential orthotopic liver transplants performed at our center between July 1996 and May 1999. Ten patients with fulminant hepatic failure were excluded from the study, leaving 99 patients. Nutritional status was determined at the time of transplantation using subjective global assessment. Wilcoxon rank sum test and rank analysis of variance were used to analyze the data. Results are reported as median (interquartile range). A P value <0.05 was considered significant. RESULTS: Intraoperative transfusion requirements of packed red blood cells and cryoprecipitate was higher in the patients with severe malnutrition in comparison to the mild and moderate groups (severe vs. moderate, 5.5+/-5.5 vs. 3.0+/-6, P=0.026; vs. mild, 1.5+/-3, P<0.0001). The severe group required more fresh-frozen plasma intraoperatively than the mild group (mild vs. severe, 0+/-2 vs. 2+/-6, P=0.0007; vs. moderate, 1+/-4, P=0.071). Patients in the severe group had longer postoperative lengths of stay compared with patients in the moderate and mild groups (severe vs. moderate, 16+/-9 days vs. 10+/-5 days, P=0.0027; vs. mild, 9+/-8 days, P=0.0006). CONCLUSIONS: Subjective global assessment is an excellent independent predictor of outcome in patients undergoing liver transplantation. Severely malnourished patients require more blood products during surgery and have prolonged postoperative length of stay in hospital. Our data suggest that if nutritional repletion is possible in patients with end-stage liver disease before transplantation, patient outcomes could be improved.


Assuntos
Transplante de Fígado , Avaliação Nutricional , Distúrbios Nutricionais/diagnóstico , Cuidados Pré-Operatórios , Transfusão de Sangue , Feminino , Humanos , Cuidados Intraoperatórios , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Distúrbios Nutricionais/fisiopatologia , Prognóstico , Índice de Gravidade de Doença , Resultado do Tratamento
11.
J Vasc Interv Radiol ; 11(7): 905-11, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10928531

RESUMO

PURPOSE: To determine whether fibrin sealant injected into the tract created by liver biopsy can be used to decrease postprocedural bleeding. An innovative delivery system was used to deploy the fibrin sealant. MATERIALS AND METHODS: Fibrin sealant is a hemostatic agent consisting of a suspension of fibrinogen and thrombin. A delivery system was devised whereby fibrin sealant could be injected into the tract created by liver biopsy. Thirty swine were randomized into three groups: control (n = 10), heparin (n = 10), and warfarin (n = 10). Each swine underwent laparotomy and was randomized to undergo three to five open liver biopsies with either a 14-gauge cutting needle in conjunction with the fibrin sealant device or a standard 14-gauge cutting needle alone. Forty-seven biopsy procedures were performed with the device; 64 biopsy procedures were performed without the device. Immediate blood loss per biopsy (mL) was estimated based on the size of the blood stain on a sponge. Specimens were assessed for sample size. RESULTS: Immediate blood loss with and without the device, respectively, was: control, 0.1 mL, 5.4 mL; heparin, 0 mL, 7 mL; warfarin, 0.1 mL, 9.3 mL. These differences were significant (P < .01) for each group of swine. In 43 of 47 biopsies (91%), the device functioned without difficulty. There was no difference in sample size when the device was used. CONCLUSIONS: The fibrin sealant device is effective in reducing bleeding after open liver biopsy in anticoagulated and nonanticoagulated swine. The promising results suggest that a trial of percutaneous liver biopsy in swine should be considered.


Assuntos
Biópsia por Agulha , Adesivo Tecidual de Fibrina/uso terapêutico , Hemostáticos/uso terapêutico , Fígado/patologia , Animais , Anticoagulantes/uso terapêutico , Biópsia por Agulha/efeitos adversos , Biópsia por Agulha/instrumentação , Sistemas de Liberação de Medicamentos , Desenho de Equipamento , Adesivo Tecidual de Fibrina/administração & dosagem , Hemorragia/prevenção & controle , Hemostáticos/administração & dosagem , Heparina/uso terapêutico , Laparotomia , Agulhas , Distribuição Aleatória , Estatísticas não Paramétricas , Suínos , Seringas , Varfarina/uso terapêutico
12.
Pflugers Arch ; 439(6): 845-52, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10784361

RESUMO

In this study we examined the effects of 3-24 h of incubation of chemically skinned rat fast-twitch muscle with the glycolytic metabolite glucose 6-phosphate (G6-P) on the contractile properties and myosin ATPase activity in single muscle fibres, and on the carbohydrate content of myosin heavy chains (MHCs). Exposure of the permeabilised muscle to 10 mM G6-P for 24 h at 22+/-1 degrees C in a rigor solution containing protease inhibitors and a reducing agent (dithiothreitol, DTT) significantly decreased maximum Ca(2+)-activated force output by 31%, lowered the Ca2+ threshold for contraction by 0.1 pCa units and produced shallower force-pCa curves compared with controls. Furthermore, under these conditions, G6-P-treated muscle displayed lower myofibrillar MgATPase activity and a markedly higher carbohydrate content of MHCs, as identified with an immunoblot protocol for glycoprotein detection. Shorter incubations under the same conditions or 24-h incubations with 5 mM G6-P generally resulted in smaller changes in the contractile activation parameters. These findings suggest that reducing sugars acting as metabolic intermediates in the glycolytic pathway can have important non-energy-related effects on the contractile activation characteristics of mammalian skeletal muscle. These effects are consistent with the glycation of muscle proteins, in particular that of the MHC.


Assuntos
Cálcio/fisiologia , Glucose-6-Fosfato/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Carboidratos/análise , Técnicas Histológicas , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Miofibrilas/enzimologia , Cadeias Pesadas de Miosina/química , Ratos , Ratos Long-Evans , Valores de Referência , Sarcômeros/ultraestrutura
13.
Perfusion ; 14(5): 389-96, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10499656

RESUMO

Conventional cardiopulmonary bypass (CPB) in neonates results in increased transfusion requirements and hemodilution. There has been little advancement in CPB for the neonatal population. There is evidence that increased priming volumes and blood product transfusion enhances inflammatory response to CPB and increases myocardial and pulmonary dysfunction. We have devised a miniaturized CPB circuit that utilizes vacuum-assisted venous drainage (VAVD) in an effort to decrease priming volume and avoid transfusion requirements. The purpose of this study was to evaluate the safety and efficacy of this miniaturized CPB system and determine the feasibility of an asanguineous prime. Ten 1-week-old piglets were randomized to five mini- and five conventional CPB pump circuits. Subjects were supported with CPB at 100 ml/kg/min, cooled to 28 degrees C, exposed to 10 min aortic crossclamp with cardioplegic arrest, rewarmed to 37 degrees C, weaned from bypass, and subjected to modified-ultrafiltration (MUF) for approximately 10 min. This method was chosen to simulate a situation with all the elements of clinical CPB. Blood transfusion trigger was a hematocrit <15 on CPB. Serum samples were obtained pre-CPB, at 15 min of CPB onset, immediately post-CPB completion, and immediately post-MUF. Indices of hemolysis (SGOT, LDH), production of inflammatory mediators (interleukin (IL)-8, tumor necrosis factor-alpha (TNFalpha)), and physiologic parameters of inflammation were measured. The overall blood requirement was significantly less in the mini-circuit compared to conventional CPB (47.0+/-5.8 ml vs 314.2+/-31.6 ml; p < 0.0001). The only significant blood requirement in the mini-circuit was to replace the volume removed for samples. During the study, mean arterial pressure (MAP) (p = 0.004), static pulmonary compliance (p = 0.04), platelets (p = 0.0003), and white blood cells (p = 0.003) significantly decreased across the groups. Lung water content (p = 0.02), TNFalpha levels (p = 0.05), and SGOT (p = 0.009) increased significantly during the study, across the groups. Among all parameters tested, except for blood requirement and hematocrit post-CPB, there were no significant differences between the two circuits. VAVD makes asanguineous prime in neonates feasible. When used in this study to miniaturize a conventional-CPB circuit, VAVD with a reconfigured neonatal CPB console and circuit resulted in no detrimental effects, and allowed for markedly decreased priming volumes and blood transfusion requirements.


Assuntos
Ponte Cardiopulmonar , Circulação Extracorpórea/instrumentação , Sucção/instrumentação , Animais , Hemodinâmica , Inflamação , Substitutos do Plasma/administração & dosagem , Suínos
14.
J Physiol ; 519 Pt 1: 177-87, 1999 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-10432348

RESUMO

1. Mechanically skinned skeletal muscle fibres from the twitch region of the iliofibularis muscle of cane toads were used to investigate the relationship between fibre glycogen content and fibre capacity to respond to transverse tubular (T-) system depolarization. 2. A large proportion of total fibre glycogen remained in mechanically skinned muscle fibres exposed to aqueous solutions. This glycogen pool (about 80% of total fibre glycogen) was very stable when the preparation was incubated in a rigor solution (pH 7.0) but decreased gradually at a rate of 0.59+/-0.20% min-1 in a relaxing solution (200 nM [Ca2+]). The rate was considerably higher (2.66+/-0.38% min(-1)) when the preparations were exposed to 30 microM [Ca2+]. An even greater rate of glycogen loss was found after T-system depolarization-induced contractions. The Ca2+-dependent loss of fibre glycogen was caused by endogenous glycogenolytic processes. 3. Silver stained SDS gels of components eluted into relaxing solution from single skinned fibres revealed a rapid (2 min) loss of parvalbumin and at least 10 other proteins varying in molecular mass between 10 and 80 kDa but there was essentially no loss of myosin heavy and light chains and actin. Subsequent elution for a further 30 min in either relaxing or maximally Ca2+-activating solution did not result in additional, appreciable detectable loss of fibre protein. 4. Depletion of fibre glycogen was associated with loss of fibre ability to respond to T-system depolarization even though the bathing solutions contained high levels of ATP (8 mM) and creatine phosphate (10 mM). 5. The capacity of mechanically skinned fibres to respond to T-system depolarization was highly positively correlated (P<0.0001) with initial fibre glycogen concentration. 6. In conclusion, the results show that (i) the capacity of skeletal muscle to respond to T-system depolarization is related directly or indirectly to the non-washable glycogen pool in fibres, (ii) this relationship holds for conditions where glycogen is not required as a source of energy and (iii) the mechanically skinned fibre preparation is well suited to study the regulation of endogenous glycogenolytic enzymes.


Assuntos
Glicogênio/metabolismo , Contração Muscular/fisiologia , Fibras Musculares Esqueléticas/fisiologia , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Bufo marinus , Estimulação Elétrica , Eletroforese em Gel de Poliacrilamida , Eletrofisiologia/métodos , Técnicas In Vitro , Potenciais da Membrana , Peso Molecular , Proteínas Musculares/isolamento & purificação , Parvalbuminas/metabolismo , Fosfocreatina/metabolismo
15.
Bioorg Med Chem Lett ; 9(8): 1137-40, 1999 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-10328300

RESUMO

The synthesis and biological evaluation of trans-2,3-dihydroraloxifene, 2, is described. The synthesis proceeds in 8 steps in 20% overall yield. Relative trans 2,3-stereochemistry is definitively established in ester 6, which is converted to the title compound via derivatization, Grignard addition, and deprotection. Evaluation in vitro shows the compound to be a potent selective estrogen receptor modulator (SERM).


Assuntos
Antagonistas de Estrogênios/farmacologia , Piperidinas/síntese química , Ligação Competitiva , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Modelos Moleculares , Piperidinas/química , Cloridrato de Raloxifeno , Células Tumorais Cultivadas
16.
Australas J Dermatol ; 39(2): 106-8, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9611381

RESUMO

A 24-year-old male presented with a 4 year history of a crusted erythematous papular eruption of the scalp and external auditory meati and a 12 month history of painful perianal ulceration. A diagnosis of Langerhans cell histiocytosis was made and confirmed by skin histology. Extensive investigation revealed no systemic involvement. Rapid improvement occurred after intravenous 2-chlorodeoxyadenosine but relapse of perianal lesions occurred within 5 months. Local radiotherapy to the perianal region resulted in a complete remission sustained over 12 months.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/terapia , Dermatopatias/diagnóstico , Dermatopatias/terapia , Adulto , Antineoplásicos/uso terapêutico , Biópsia , Cladribina/uso terapêutico , Terapia Combinada , Seguimentos , Humanos , Masculino , Radioterapia , Pele/patologia
17.
Food Addit Contam ; 15(1): 61-71, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9534872

RESUMO

The distribution of nine pesticides between the juice and pulp of carrots and tomatoes during home culinary practices was investigated. Tomato and carrot pulp contained a higher percentage of all pesticide residues, except for mancozeb in tomatoes. Although there was a difference in the relative distribution of the pesticides between the commodities with greater amounts present in the pulp of tomatoes, the pesticides followed a similar trend in both. A relationship between the pulp/juice distribution and water solubility of the pesticide was apparent. Pesticides with the highest water solubility were present to a greater extent in the juice. An exception was noted in the case of diazinon and parathion, which were present in higher amounts in the pulp than their water solubility would suggest. The percent residue in the pulp ranged from 56.4 to 75.2% for carrots, and 49.7 to 95.4% for tomatoes. Residues in the juice prepared from washed commodities ranged from not detected to 0.83 microgram/g. Washing of the produce removed more residue from carrots than from tomatoes, but it did not affect the relative distribution of the residues. The behaviour and fate of the chemical varied with the pesticide as well as the crop.


Assuntos
Daucus carota/química , Manipulação de Alimentos , Resíduos de Praguicidas/análise , Solanum lycopersicum/química , Contaminação de Alimentos , Fungicidas Industriais/análise , Humanos , Inseticidas/análise , Água
18.
J Synchrotron Radiat ; 5(Pt 1): 37-47, 1998 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16687799

RESUMO

A simple approach for producing a high-coherent-flux X-ray beam for small-angle-scattering studies used at the Troika beamline of the European Synchrotron Radiation Facility is reported. For such small-angle studies it is permissible to reduce the longitudinal coherence .length of the beam, thus increasing the energy bandpass and intensity of the beam, because there is only a small optical path-length difference. By using mirrors and filters to cut unwanted energies from the undulator harmonic structure, a high-flux beam of >10(9) photons s(-1) through a 5 micron-diameter pinhole at 8.2 keV with a bandpass of 1.3% can be produced. The coherent properties of this beam have been measured by analyzing a static speckle pattern from an aerogel sample imaged by a directly illuminated CCD camera. The speckle size and contrast are compared with the expected values based on a statistical analysis of the intensity distribution of speckle patterns obtained using partially coherent conditions. The expected widths of the spatial autocorrelation are found, but there is an apparent incoherent fraction of the beam which reduces the measured contrast. The method presented is to be used as a tool to optimize conditions for diffraction experiments using coherent X-rays.

19.
Ann Surg ; 226(3): 324-34; discussion 334-5, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9339939

RESUMO

OBJECTIVE: The authors evaluated the response to extended cervicomediastinal thymectomy as a component of the integrated management of patients with myasthenia gravis in a large series of patients from a single institution. The authors evaluated the response to therapy with respect to a graded, multivariate, ordinal scale chosen to reflect the full range of the disease's manifestations. SUMMARY BACKGROUND DATA: A number of series, of varying sizes, describe the response of patients with myasthenia gravis to thymectomy primarily with respect to the bivariate endpoint of the presence or absence of "remission." These studies fail to describe the full spectrum of postoperative disease severity and have been unable to quantify definitively the influence of putative prognostic variables, nor to assess definitively the statistical significance of apparent improvements over time. METHODS: The authors evaluated 202 consecutive patients who underwent trans-sternal thymectomy for symptomatic myasthenia gravis from 1969 through 1996 at the Johns Hopkins Hospital. The response to surgery, combined with postoperative medical therapy, was evaluated by a standardized scale reflecting the full spectrum of the disease. These data were analyzed by a novel mean multivariate regression analysis, which allowed the quantification of the statistical significance of apparent responses over time and the evaluation of the independent influence of each of nine putative prognostic indicators. RESULTS: There was no perioperative mortality and a 33% perioperative morbidity. There was a marked clinical response at 6 months to 1 year after surgery that was sustained for at least 10 years thereafter. The median increment of improvement was two (of five) classes. Eighty-six percent and 83% of the patients had improved by at least one class at 5 and 10 years, respectively. These changes were statistically significant (p < 0.001). Whereas the use of extended cervicomediastinal thymectomy was associated with a greater than twofold chance of improvement, compared to conventional trans-sternal thymectomy, neither the pathologic diagnosis (presence of thymoma) nor the age at surgery proved to be negative predictors of postoperative response. CONCLUSIONS: Extended cervicomediastinal thymectomy is the procedure of choice as a component of the integrated management of myasthenia gravis, with significant improvement seen in the group as a whole, as well as in subgroups of patients with thymoma and those older than 40 years of age.


Assuntos
Miastenia Gravis/cirurgia , Timectomia/métodos , Adolescente , Adulto , Idoso , Criança , Intervalos de Confiança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/classificação , Razão de Chances , Prognóstico , Análise de Regressão , Reoperação , Fatores de Risco , Infecção da Ferida Cirúrgica/etiologia , Taxa de Sobrevida , Timectomia/efeitos adversos , Timectomia/mortalidade , Resultado do Tratamento
20.
Biotechnol Bioeng ; 48(3): 190-6, 1995 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-18623477

RESUMO

Humicola lanuginosa lipase (HIL) and Rhizomucor miehei lipase (RrnL), isolated from commercial preparations of Lipolase and Lipozyme, respectively, were solubilized in AOT-stabilized water-in-oil (w/o) microemulsions in n-heptane and aspects of their hydrolysis and condensation activity examined. The temperature dependence of HIL hydrolysis activity in unbuffered R = 10 microemulsions matched very closely that for tributyrin hydrolysis by Lipolase in an aqueous emulsion assay. Apparent activation energies were measured as 13 +/- 2 and 15 +/- 2 kJ mol / respectively. Condensation activity, however, was essentially independent of temperature over the range 5 degrees to 37 degrees C. The stability of HIL over a 30-day period was very good at all pH levels (6.1, 7.2, 9.3) and R values studied (5, 7.5, 10, 20), except when high pHs and low R values were combined. The excellent stability was reflected by the linearity of the productivity profiles which facilitate system optimization. The temperature dependence of RmL hydrolysis activity toward pNPC(4) showed a maximum at 40 degrees C and an apparent E(act) = 20 +/- 2 kJ mol(-1) was calculated based on the linear region of the profile (5 degrees to 40 degrees C). RmL esterification activity showed only a slight dependence on temperature over the studied range (0 degrees to 40 degrees C) and an apparent E(act) = 5 +/- 1 kJ mol(-1) was measured for octyl decanoate synthesis. Both RmL and HIL, therefore, have potential for application in low temperature biotransformations in microemulsion-based media. The stability of RmL over a 30-day period was good in R = 7.5 and R = 10 microemulsions containing pH 6.1 buffer, and this was reflected in the linearity of their respective productivity profiles. RmL stability was markedly poorer at more alkaline pH, however, and proved to be sensitive to relatively small changes in the R value.

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