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1.
Nat Commun ; 15(1): 63, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167404

RESUMO

Avapritinib is the only potent and selective inhibitor approved for the treatment of D842V-mutant gastrointestinal stromal tumors (GIST), the most common primary mutation of the platelet-derived growth factor receptor α (PDGFRA). The approval was based on the NAVIGATOR trial, which revealed overall response rates of more than 90%. Despite this transformational activity, patients eventually progress, mostly due to acquired resistance mutations or following discontinuation due to neuro-cognitive side effects. These patients have no therapeutic alternative and face a dismal prognosis. Notable, little is known about this drug's binding mode and its medicinal chemistry development, which is instrumental for the development of the next generation of drugs. Against this background, we solve the crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Pirazóis/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Antineoplásicos/farmacologia
2.
Pregnancy Hypertens ; 30: 113-123, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36174484

RESUMO

BACKGROUND: Self-monitoring of blood pressure (BP) has been shown to be effective at improving BP control in the general population. The OPTIMUM-BP feasibility study was a prospective randomised controlled trial of self-monitoring of BP (SMBP) during hypertensive pregnancy. OBJECTIVE: To explore experiences, perceptions, and use of the OPTIMUM-BP self-monitoring intervention. STUDY DESIGN: Qualitative study within the OPTIMUM-BP feasibility trial. Semi-structured interviews with a purposive sample of pregnant women with chronic hypertension (n = 24) and their clinicians (n = 8) as well as 38 ethnographic observations of antenatal visits. RESULTS: Women found self-monitoring of BP feasible and acceptable and were highly motivated and pro-active in their monitoring, reporting greater control and knowledge of BP and reassurance. Women's persistence with SMBP was driven by a perceived need to safeguard the pregnancy, particularly among those taking antihypertensive medication. Clinicians also described the intervention as acceptable, though BP variability could cause uncertainty. Clinicians used different heuristics to integrate home and clinic readings. Observations suggested close working relationships between women and clinicians were key for confident integration of self-monitoring. CONCLUSIONS: Self-monitoring of BP was acceptable both to pregnant women with hypertension and their clinicians. More research is needed to understand BP variability within pregnancy to help interpret and integrate home BP readings for improved BP management. Clinical pathways that use BP self-monitoring should aim to maintain the continuity of care and relationships that are valued and appear pivotal for the confident and safe use of self-monitoring in pregnancy.


Assuntos
Hipertensão , Pré-Eclâmpsia , Feminino , Humanos , Gravidez , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Estudos Prospectivos , Hipertensão/tratamento farmacológico
3.
Anal Chem ; 94(15): 6017-6025, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35385261

RESUMO

Single-cell proteomics (SCP) has great potential to advance biomedical research and personalized medicine. The sensitivity of such measurements increases with low-flow separations (<100 nL/min) due to improved ionization efficiency, but the time required for sample loading, column washing, and regeneration in these systems can lead to low measurement throughput and inefficient utilization of the mass spectrometer. Herein, we developed a two-column liquid chromatography (LC) system that dramatically increases the throughput of label-free SCP using two parallel subsystems to multiplex sample loading, online desalting, analysis, and column regeneration. The integration of MS1-based feature matching increased proteome coverage when short LC gradients were used. The high-throughput LC system was reproducible between the columns, with a 4% difference in median peptide abundance and a median CV of 18% across 100 replicate analyses of a single-cell-sized peptide standard. An average of 621, 774, 952, and 1622 protein groups were identified with total analysis times of 7, 10, 15, and 30 min, corresponding to a measurement throughput of 206, 144, 96, and 48 samples per day, respectively. When applied to single HeLa cells, we identified nearly 1000 protein groups per cell using 30 min cycles and 660 protein groups per cell for 15 min cycles. We explored the possibility of measuring cancer therapeutic targets with a pilot study comparing the K562 and Jurkat leukemia cell lines. This work demonstrates the feasibility of high-throughput label-free single-cell proteomics.


Assuntos
Peptídeos , Proteoma , Cromatografia Líquida/métodos , Células HeLa , Humanos , Peptídeos/análise , Projetos Piloto , Proteoma/análise
4.
Pregnancy Hypertens ; 26: 54-61, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34508949

RESUMO

OBJECTIVE: This study aimed to understand the views and practice of obstetricians regarding self-monitoring for hypertensive disorders of pregnancy (blood pressure (BP) and proteinuria), the potential for self-management (including actions taken on self-monitored parameters) and to understand the impact of the COVID-19 pandemic on such views. DESIGN: Cross-sectional online survey pre- and post- the first wave of the COVID-19 pandemic. SETTING AND SAMPLE: UK obstetricians recruited via an online portal. METHODS: A survey undertaken in two rounds: December 2019-January 2020 (pre-pandemic), and September-November 2020 (during pandemic) RESULTS: 251 responses were received across rounds one (150) and two (101). Most obstetricians considered that self-monitoring of BP and home urinalysis had a role in guiding clinical decisions and this increased significantly following the first wave of the COVID-19 pandemic (88%, (132/150) 95%CI: 83-93% first round vs 96% (95%CI: 92-94%), (97/101), second round; p = 0.039). Following the pandemic, nearly half were agreeable to women self-managing their hypertension by using their own readings to make a pre-agreed medication change themselves (47%, 47/101 (95%CI: 37-57%)). CONCLUSIONS: A substantial majority of UK obstetricians considered that self-monitoring had a role in the management of pregnancy hypertension and this increased following the pandemic. Around half are now supportive of women having a wider role in self-management of hypertensive treatment. Maximising the potential of such changes in pregnancy hypertension management requires further work to understand how to fully integrate women's own measurements into clinical care.


Assuntos
Atitude do Pessoal de Saúde , COVID-19/epidemiologia , Hipertensão Induzida pela Gravidez/terapia , Pandemias , Autogestão/métodos , Adulto , Monitorização Ambulatorial da Pressão Arterial/métodos , Estudos Transversais , Feminino , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Reino Unido/epidemiologia
5.
Inorg Chem ; 60(17): 13000-13010, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34415750

RESUMO

The infiltration of palladium and platinum nanoparticles (NPs) into the mesoporous metal-organic framework (MOF) CYCU-3 through chemical vapor infiltration (CVI) and incipient wetness infiltration (IWI) processes was systematically explored as a means to design novel NP@MOF composite materials for potential hydrogen storage applications. We employed a traditional CVI process and a new ″green″ IWI process using methanol for precursor infiltration and reduction under mild conditions. Transmission electron microscopy-based direct imaging techniques combined with synchrotron-based powder diffraction (SPD), energy-dispersive X-ray spectroscopy, and physisorption analysis reveal that the resulting NP@MOF composites combine key NP and MOF properties. Room temperature hydrogen adsorption capacities of 0.95 and 0.20 mmol/g at 1 bar and 2.9 and 1.8 mmol/g at 100 bar are found for CVI and IWI samples, respectively. Hydrogen spillover and/or physisorption are proposed as the dominating adsorption mechanisms depending on the NP infiltration method. Mechanistic insights were obtained through the crystallographic means using SPD-based difference envelope density analysis, providing previously underexplored details on NP@MOF preparations. Consequently, important host-guest correlations influencing the global hydrogen adsorption properties are discussed, and they demonstrate that employing MOFs as platforms for NPs is an alternative approach to the development of versatile materials for improving current hydrogen storage technologies.

6.
Blood ; 130(24): 2678-2681, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29021229

RESUMO

Sepsis concurrently activates both coagulation and complement systems. Although complement activation by bacteria is well documented, work in mice and in vitro suggests that coagulation proteases can directly cleave complement proteins. We aimed to determine whether generation of coagulation proteases in vivo can activate the complement cascade in 2 highly coagulopathic models. We compared temporal changes in activation biomarkers of coagulation (thrombin-antithrombin [TAT]), fibrinolysis (plasmin-antiplasmin [PAP]), and complement (C3b, C5a, C5b-9) in baboons infused with factor Xa (FXa) and phospholipids (FXa/phosphatidylcholine-phosphatidylserine [PCPS]) vs LD100 Escherichia coli We found that, albeit with different timing, both FXa/PCPS and E coli infusion led to robust thrombin and plasmin generation. Conversely, only E coli challenge activated the complement system, reaching a maximum at 2 hours postchallenge during the peaks of lipopolysaccharide and bacteremia but not of TAT and PAP. Despite inducing a strong burst of thrombin and plasmin, FXa/PCPS infusion did not produce measurable levels of complement activation in vivo. Similarly, ex vivo incubation of baboon serum with thrombin, plasmin, or FXa did not show noticeable complement cleavage unless supraphysiologic amounts of enzymes were used. Our results suggest that in vivo-generated thrombin and plasmin do not directly activate the complement in nonhuman primates.


Assuntos
Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Fibrinolisina/imunologia , Trombina/imunologia , Animais , Ativação do Complemento/efeitos dos fármacos , Proteínas do Sistema Complemento/metabolismo , Escherichia coli/imunologia , Escherichia coli/metabolismo , Fator Xa/imunologia , Fator Xa/farmacologia , Fibrinolisina/metabolismo , Humanos , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Papio , Fosfatidilcolinas/imunologia , Fosfatidilcolinas/farmacologia , Fosfatidilserinas/imunologia , Fosfatidilserinas/farmacologia , Trombina/metabolismo
7.
Obes Rev ; 18(3): 335-349, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28117945

RESUMO

AIM: We conducted a systematic review of qualitative studies to examine the strategies people employ as part of self-directed weight loss attempts, map these to an existing behaviour change taxonomy and explore attitudes and beliefs surrounding these strategies. METHODS: Seven electronic databases were searched in December 2015 for qualitative studies in overweight and obese adults attempting to lose weight through behaviour change. We were interested in strategies used by participants in self-directed efforts to lose weight. Two reviewers extracted data from included studies. Thematic and narrative synthesis techniques were used. RESULTS: Thirty one studies, representing over 1,000 participants, were included. Quality of the included studies was mixed. The most commonly covered types of strategies were restrictions, self-monitoring, scheduling, professional support and weight management aids. With the exception of scheduling, for which participant experiences were predominantly positive, participants' attitudes and beliefs surrounding implementation of these groups of strategies were mixed. Two new groups of strategies were added to the existing taxonomy: reframing and self-experimentation. CONCLUSIONS: This review demonstrates that at present, interventions targeting individuals engaged in self-management of weight do not necessarily reflect lived experiences of self-directed weight loss.


Assuntos
Cognição , Obesidade/psicologia , Obesidade/terapia , Sobrepeso/psicologia , Sobrepeso/terapia , Redução de Peso , Humanos , Autocuidado
8.
QJM ; 109(10): 669-674, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27026699

RESUMO

BACKGROUND: There is a paucity of nationally representative data in the area of heart failure (HF) and physical function (PF). AIM: Examine the relationship(s) between HF and PF in a nationally representative sample of United States (US) adults. DESIGN: Cross-section analysis of US adults. METHODS: Sample (n = 6623) included adult (≥40 years of age) participants from the 1999-2006 National Health and Nutrition Examination Survey. Participants reporting HF answered questions related to their abilities to accomplish specific upper extremity and lower extremity tasks, and household chores. RESULTS: Prevalence estimates of reporting much difficulty or the inability to stand from an armless chair was 9.9% and 4.3% (P = 0.002) in those with and without HF, respectively. Similar estimates were revealed for much difficulty or inability to lift or carry 10 pounds (16.8% and 8.6%, P = 0.0004) and much difficulty or inability to do household chores (13.3% and 6.1%, P = 0.0008). Following adjustments participants reporting HF had significantly greater odds of reporting much difficulty or the inability to stand from an armless chair [odds ratio (OR) 1.93; 95% confidence intervals (CI) 1.25, 2.96], much difficulty or the inability to lift or carry 10 lbs (OR 1.90; 95% CI 1.36, 2.65) and much difficulty or inability to do household chores (OR 2.06; 95% CI 1.41, 3.02) compared with participants not reporting HF. CONCLUSIONS: Findings suggest US adults reporting HF are more likely to report poorer PF.


Assuntos
Atividades Cotidianas , Insuficiência Cardíaca/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/reabilitação , Humanos , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Atividade Motora/fisiologia , Inquéritos Nutricionais , Prevalência , Autorrelato , Estados Unidos/epidemiologia
9.
J Cell Mol Med ; 20(6): 1170-81, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26990127

RESUMO

Sphingosine 1-phosphate (S1P) is an important regulator of vascular integrity and immune cell migration, carried in plasma by high-density lipoprotein (HDL)-associated apolipoprotein M (apoM) and by albumin. In sepsis, the protein and lipid composition of HDL changes dramatically. The aim of this study was to evaluate changes in S1P and its carrier protein apoM during sepsis. For this purpose, plasma samples from both human sepsis patients and from an experimental Escherichia coli sepsis model in baboons were used. In the human sepsis cohort, previously studied for apoM, plasma demonstrated disease-severity correlated decreased S1P levels, the profile mimicking that of plasma apoM. In the baboons, a similar disease-severity dependent decrease in plasma levels of S1P and apoM was observed. In the lethal E. coli baboon sepsis, S1P decreased already within 6-8 hrs, whereas the apoM decrease was seen later at 12-24 hrs. Gel filtration chromatography of plasma from severe human or baboon sepsis on Superose 6 demonstrated an almost complete loss of S1P and apoM in the HDL fractions. S1P plasma concentrations correlated with the platelet count but not with erythrocytes or white blood cells. The liver mRNA levels of apoM and apoA1 decreased strongly upon sepsis induction and after 12 hr both were almost completely lost. In conclusion, during septic challenge, the plasma levels of S1P drop to very low levels. Moreover, the liver synthesis of apoM decreases severely and the plasma levels of apoM are reduced. Possibly, the decrease in S1P contributes to the decreased endothelial barrier function observed in sepsis.


Assuntos
Apolipoproteínas/metabolismo , Escherichia coli/fisiologia , Lipocalinas/metabolismo , Lisofosfolipídeos/metabolismo , Sepse/metabolismo , Sepse/microbiologia , Esfingosina/análogos & derivados , Animais , Apolipoproteínas M , Plaquetas/metabolismo , Estudos de Casos e Controles , Cromatografia em Gel , Contagem de Colônia Microbiana , Eritrócitos/metabolismo , Humanos , Rim/metabolismo , Leucócitos/metabolismo , Papio , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sepse/sangue , Esfingosina/metabolismo , Transcrição Gênica
10.
J Cell Mol Med ; 19(11): 2549-63, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26337158

RESUMO

Acute respiratory distress syndrome (ARDS) induced by severe sepsis can trigger persistent inflammation and fibrosis. We have shown that experimental sepsis in baboons recapitulates ARDS progression in humans, including chronic inflammation and long-lasting fibrosis in the lung. Complement activation products may contribute to the fibroproliferative response, suggesting that complement inhibitors are potential therapeutic agents. We have been suggested that treatment of septic baboons with compstatin, a C3 convertase inhibitor protects against ARDS-induced fibroproliferation. Baboons challenged with 10(9) cfu/kg (LD50) live E. coli by intravenous infusion were treated or not with compstatin at the time of challenge or 5 hrs thereafter. Changes in the fibroproliferative response at 24 hrs post-challenge were analysed at both transcript and protein levels. Gene expression analysis showed that sepsis induced fibrotic responses in the lung as early as 24 hrs post-bacterial challenge. Immunochemical and biochemical analysis revealed enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Specific inhibition of complement with compstatin down-regulated sepsis-induced fibrosis genes, including transforming growth factor-beta (TGF-ß), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 1 (TIMP1), various collagens and chemokines responsible for fibrocyte recruitment (e.g. chemokine (C-C motif) ligand 2 (CCL2) and 12 (CCL12)). Compstatin decreased the accumulation of myofibroblasts and proliferating cells, reduced the production of fibrosis mediators (TGF-ß, phospho-Smad-2 and CTGF) and inhibited collagen deposition. Our data demonstrate that complement inhibition effectively attenuates collagen deposition and fibrotic responses in the lung after severe sepsis. Inhibiting complement could prove an attractive strategy for preventing sepsis-induced fibrosis of the lung.


Assuntos
Bacteriemia/tratamento farmacológico , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Infecções por Escherichia coli/tratamento farmacológico , Pulmão/patologia , Peptídeos Cíclicos/uso terapêutico , Animais , Bacteriemia/imunologia , Bacteriemia/patologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/fisiopatologia , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/patologia
11.
Opt Lett ; 40(17): 4186-9, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26368743

RESUMO

An interband cascade laser (ICL) operating at 3.7 µm has been used to perform multimode absorption spectroscopy, MUMAS, at scan rates up to 10 kHz. Line widths of individual modes in the range 10-80 MHz were derived from isolated lines in the MUMAS signatures of HCl. MUMAS data for methane covering a spectral range of 30 nm yielded a detection level of 30 µbar·m for 1 s measurement time at 100 Hz. Simultaneous detection of methane, acetylene, and formaldehyde in a gas mixture containing all three species is reported.

12.
Neurobiol Stress ; 1: 89-99, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25436222

RESUMO

Research on the neurobiology of the stress response in animals has led to successful new treatments for Post-Traumatic Stress Disorder (PTSD) in humans. Basic research has found that high levels of catecholamine release during stress rapidly impair the top-down cognitive functions of the prefrontal cortex (PFC), while strengthening the emotional and habitual responses of the amygdala and basal ganglia. Chronic stress exposure leads to dendritic atrophy in PFC, dendritic extension in the amygdala, and strengthening of the noradrenergic (NE) system. High levels of NE release during stress engage low affinity alpha-1 adrenoceptors, (and likely beta-1 adrenoceptors), which rapidly reduce the firing of PFC neurons, but strengthen amygdala function. In contrast, moderate levels of NE release during nonstress conditions engage higher affinity alpha-2A receptors, which strengthen PFC, weaken amygdala, and regulate NE cell firing. Thus, either alpha-1 receptor blockade or alpha-2A receptor stimulation can protect PFC function during stress. Patients with PTSD have signs of PFC dysfunction. Clinical studies have found that blocking alpha-1 receptors with prazosin, or stimulating alpha-2A receptors with guanfacine or clonidine can be useful in reducing the symptoms of PTSD. Placebo-controlled trials have shown that prazosin is helpful in veterans, active duty soldiers and civilians with PTSD, including improvement of PFC symptoms such as impaired concentration and impulse control. Open label studies suggest that guanfacine may be especially helpful in treating children and adolescents who have experienced trauma. Thus, understanding the neurobiology of the stress response has begun to help patients with stress disorders.

13.
Eur J Neurol ; 21(10): 1258-67, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24861479

RESUMO

Transient ischaemic attack (TIA) and minor stroke are characterized by short-lasting symptoms; however, anecdotal and empirical evidence suggests that these patients experience ongoing cognitive/psychological impairment for which they are not routinely treated. The aims were (i) to investigate the prevalence and time course of fatigue, anxiety, depression, post-traumatic stress disorder(PTSD) and cognitive impairment following TIA/minor stroke; (ii) to explore the impact on quality of life (QoL), change in emotions and return to work; and (iii) to identify where further research is required and potentially inform an intervention study. A systematic review of MEDLINE, EMBASE, PSYCINFO, CINAHL, the Cochrane libraries and the grey literature between January 1993 and April 2013 was undertaken. Literature was screened and data were extracted by two independent reviewers. Studies were included of adult TIA/minor stroke participants with any of the outcomes of interest: fatigue, anxiety, depression, PTSD, cognitive impairment, QoL, change in emotions and return to work. Random-effects meta-analysis pooled outcomes by measurement tool. Searches identified 5976 records, 289 were assessed for eligibility and 31 studies were included. Results suggest high levels of cognitive impairment and depression post-TIA/minor stroke which decreased over time. However, frequencies varied between studies. Limited information was available on anxiety, PTSD and fatigue. Meta-analysis revealed that the measurement tool administered influenced the prevalence of cognitive impairment: Mini-Mental State Examination 17% [95% confidence interval (CI) 7, 26]; neuropsychological test battery 39% (95% CI 28, 50); Montreal Cognitive Assessment 54% (95% CI 43, 66). There is evidence to suggest that TIA/minor stroke patients may experience residual impairments; however, results should be interpreted with caution because of the few high quality studies. Notwithstanding, it is important to raise awareness of potential subtle but meaningful residual impairments.


Assuntos
Ansiedade/etiologia , Transtornos Cognitivos/etiologia , Depressão/etiologia , Fadiga/etiologia , Ataque Isquêmico Transitório/complicações , Transtornos de Estresse Pós-Traumáticos/etiologia , Acidente Vascular Cerebral/complicações , Ansiedade/epidemiologia , Transtornos Cognitivos/epidemiologia , Depressão/epidemiologia , Fadiga/epidemiologia , Humanos , Ataque Isquêmico Transitório/epidemiologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Acidente Vascular Cerebral/epidemiologia
14.
Obes Rev ; 14(12): 975-88, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23848939

RESUMO

Schools are increasingly recognized as an ideal setting for interventions to tackle childhood obesity. A better understanding of the views of key stakeholders would help to engage schools and inform the feasibility of such interventions in practice. This meta-synthesis of 18 qualitative studies explores the views of parents, school staff, school governors, school nurses and students on the role of the primary school in preventing childhood obesity. Six categories emerged: 'School as a key setting'; 'What schools should be doing to promote healthy eating (HE)'; 'What schools should be doing to promote physical activity (PA)'; 'General barriers'; 'Barriers to promoting HE at school'; and 'Barriers to promoting PA at school'. Thirty-seven finer-level themes emerged within these categories. Stakeholders agreed on the key role of the primary school as a setting for obesity prevention, the importance of schools providing and promoting opportunities for HE and PA, and the need for schools to work with parents. Some perceived barriers could be overcome at school level, e.g. using unhealthy foods as rewards/fundraisers or withholding PA for bad behaviour. Leadership and guidance from government were considered to be needed to counteract other observed barriers, particularly regarding school canteens, support for parents and time for PA.


Assuntos
Relações Comunidade-Instituição , Promoção da Saúde/métodos , Obesidade Infantil/prevenção & controle , Serviços de Saúde Escolar/organização & administração , Instituições Acadêmicas/normas , Criança , Fenômenos Fisiológicos da Nutrição Infantil , Feminino , Política de Saúde , Promoção da Saúde/normas , Disparidades nos Níveis de Saúde , Humanos , Liderança , Masculino , Política Nutricional , Pesquisa Qualitativa , Serviços de Saúde Escolar/normas
15.
Oper Dent ; 38(5): 528-38, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23391035

RESUMO

PURPOSE: This laboratory study evaluated an experimental 1-second initial partial polymerization (IPP) technique using Fuji II LC vs the manufacturer's standard placement (control), both with and without Fuji Coat, relative to microleakage. METHODS: Class V restorative preparations were placed on the buccal and lingual aspects of 30 permanent, caries-free and restoration-free, third molar teeth. Fuji II LC restorations were placed either following manufacturer-specified guidelines or IPP for 1 second prior to contouring and full light curing. Half of the restorations were placed using the IPP experimental technique and half of the teeth were finished using Fuji Coat LC. Following thermocycling, specimens were sectioned and dye penetration was measured. SPSS 16 was used for statistical analysis (p<0.05). RESULTS: Mean microleakage results: experimental/varnish (0.08 ± 0.15 mm), control/varnish (0.17 ± 0.35 mm), experimental/nonvarnish (0.33 ± 0.33 mm), and control/nonvarnish (0.58 ± 0.47 mm). Univariate analysis of variance demonstrated significantly less microleakage for the experimental technique (p<0.001), use of finishing varnish (p<0.001), and the combination of experimental/varnish (p=0.013). CONCLUSIONS: The initial partial polymerization technique of Fuji II LC placement significantly reduces microleakage. Fuji Coat LC results in further diminished microleakage.


Assuntos
Infiltração Dentária/prevenção & controle , Resinas Sintéticas/administração & dosagem , Lâmpadas de Polimerização Dentária , Restauração Dentária Permanente/métodos , Cimentos de Ionômeros de Vidro/uso terapêutico , Humanos , Dente Molar , Polimerização , Resinas Sintéticas/uso terapêutico
16.
Biochim Biophys Acta ; 1823(10): 1720-30, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22705351

RESUMO

Neuronal cells use the process of vesicle trafficking to manipulate the populations of neurotransmitter receptors and other membrane proteins. Long term potentiation (LTP) is a long-lived increase in synaptic strength between neurons and increases postsynaptic dendritic spine size and the concentration of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptor (AMPAR) located in the postsynaptic density. AMPAR is removed from the cell surface via clathrin-mediated endocytosis. While the adaptor protein 2 (AP2) complex of endocytosis seems to have the components needed to allow temporal and spatial regulations of internalization, many accessory proteins are involved, such as epidermal growth factor receptor phosphorylation substrate 15 (Eps15). A sequence of repeats in the Eps15 protein is known as the Eps15 homology (EH) domain. It has affinity for asparagine-proline-phenylalanine (NPF) sequences that are contained within vesicle trafficking proteins such as epsin, Rab11 family interacting protein 2 (Rab11-FIP2), and Numb. After endocytosis, a pool of AMPAR is stored in the endosomal recycling compartment that can be transported to the dendritic spine surface upon stimulation during LTP for lateral diffusion into the postsynaptic density. Rab11 and the Eps15 homologue EHD1 are involved in receptor recycling. EHD family members are also involved in transcytosis of the neuronal cell adhesion molecule neuron-glia cell adhesion molecule (NgCAM) from the somatodendritic compartment to the axon. Neurons have a unique morphology comprising many projections of membrane that is constructed in part by the effects of the Eps15 homologue, intersectin. Morphogenesis in the somatodendritic compartment is becoming better understood, but there is still much exciting territory to explore, especially regarding the roles of various EH domain-NPF interactions in endocytic and recycling processes.


Assuntos
Compartimento Celular , Dendritos/metabolismo , Modelos Biológicos , Animais , Clatrina/metabolismo , Endocitose , Humanos , Vesículas Transportadoras/metabolismo
17.
J Thromb Thrombolysis ; 33(4): 412-5, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22228479

RESUMO

Activated thrombin-activatable fibrinolysis inhibitor (TAFIa or CPU) is a carboxypeptidase that is able to attenuate fibrinolysis. Although its role in fibrinolysis and inflammation has been studied extensively in vitro, its levels and subsequent effect in vivo has not been studied to the same extent. Using our recently developed assay that is specific for TAFIa, we were able to quantify its levels in plasma samples obtained from an Escherichia coli (E. coli) challenged baboon sepsis model. TAFIa levels accumulated appeared to be E. coli dose dependent, where the lethal dose of 10(10) CFU/kg generated a peak TAFIa level of 24 nM by 2 h, which represents almost 32% of total plasma level of its precursor, thrombin-activatable fibrinolysis inhibitor (TAFI or proCPU). Furthermore, our data suggest that there is continual TAFI activation under lethal level of E. coli as the apparent half-life of TAFIa is increased from 8 min to 2.2 h. Two sublethal doses of 10(8) and 10(6) CFU/kg generated peak TAFIa levels of 1.1 and 0.4 nM, respectively, both by 6 h. Taken together, our data show that TAFIa is generated at systemic levels, in a dose-dependent manner, that can substantially affect both fibrinolysis and inflammatory response in the E. coli challenged baboon sepsis model.


Assuntos
Carboxipeptidase B2/sangue , Infecções por Escherichia coli/sangue , Escherichia coli , Sepse/sangue , Animais , Modelos Animais de Doenças , Ativação Enzimática , Masculino , Papio cynocephalus , Sepse/microbiologia , Fatores de Tempo
18.
J Cell Mol Med ; 16(4): 672-82, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21972970

RESUMO

We review our baboon models of Escherichia coli sepsis that mimic, respectively, the shock/disseminated intravascular coagulation (DIC) and organ failure variants of severe sepsis, and analyse the pathophysiologic processes that are unique to each. The multi-stage, multi-factorial characteristics of severe sepsis develop as a result of the initial insult, which - depending on its intensity - activates components of the intravascular compartment leading to overwhelming shock/DIC; or initiates a sequence of events involving both the intra- and extravascular (tissues) compartments that lead to organ failure. In the latter case, the disorder passes through two stages: an initial inflammatory/coagulopathic intravascular first stage triggered by E. coli, followed by an extravascular second stage, involving components unique to each organ and triggered by ischemia/reperfusion (oxidative stress and histone release). Although a myriad of overlapping cellular and molecular components are involved, it is the context in which these components are brought into play that determine whether shock/DIC or organ failure predominate. For example, inflammatory and thrombotic responses amplified by thrombin in the first case whereas similar responses are amplified by complement activation products in the second. Rather than blocking specific mediators, we found that attenuation of the thrombin and complement amplification pathways can effectively reverse the shock/DIC and organ failure exhibited by the LD(100) and LD(50) E. coli models of severe sepsis, respectively. Translation of these concepts to successful intervention in the respective baboon models of E. coli sepsis and the application to their clinical counterparts is described.


Assuntos
Modelos Animais de Doenças , Infecções por Escherichia coli/fisiopatologia , Infecções por Escherichia coli/terapia , Sepse/fisiopatologia , Sepse/terapia , Animais , Infecções por Escherichia coli/microbiologia , Estresse Oxidativo , Papio , Sepse/microbiologia
19.
Blood ; 116(6): 1002-10, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20466856

RESUMO

Severe sepsis leads to massive activation of coagulation and complement cascades that could contribute to multiple organ failure and death. To investigate the role of the complement and its crosstalk with the hemostatic system in the pathophysiology and therapeutics of sepsis, we have used a potent inhibitor (compstatin) administered early or late after Escherichia coli challenge in a baboon model of sepsis-induced multiple organ failure. Compstatin infusion inhibited sepsis-induced blood and tissue biomarkers of complement activation, reduced leucopenia and thrombocytopenia, and lowered the accumulation of macrophages and platelets in organs. Compstatin decreased the coagulopathic response by down-regulating tissue factor and PAI-1, diminished global blood coagulation markers (fibrinogen, fibrin-degradation products, APTT), and preserved the endothelial anticoagulant properties. Compstatin treatment also improved cardiac function and the biochemical markers of kidney and liver damage. Histologic analysis of vital organs collected from animals euthanized after 24 hours showed decreased microvascular thrombosis, improved vascular barrier function, and less leukocyte infiltration and cell death, all consistent with attenuated organ injury. We conclude that complement-coagulation interplay contributes to the progression of severe sepsis and blocking the harmful effects of complement activation products, especially during the organ failure stage of severe sepsis is a potentially important therapeutic strategy.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Proteínas Inativadoras do Complemento/farmacologia , Infecções por Escherichia coli , Insuficiência de Múltiplos Órgãos/prevenção & controle , Peptídeos Cíclicos/farmacologia , Sepse , Animais , Biomarcadores/sangue , Coagulação Sanguínea/imunologia , Pressão Sanguínea/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Proteínas Inativadoras do Complemento/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Infecções por Escherichia coli/sangue , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/imunologia , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/imunologia , Papio , Sepse/sangue , Sepse/tratamento farmacológico , Sepse/imunologia
20.
Nat Med ; 15(11): 1318-21, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19855397

RESUMO

Hyperinflammatory responses can lead to a variety of diseases, including sepsis. We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage and macro- and microvascular thrombosis. We detected histone in the circulation of baboons challenged with Escherichia coli, and the increase in histone levels was accompanied by the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co-infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality, which was reversed by treatment with antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.


Assuntos
Líquido Extracelular/metabolismo , Histonas/metabolismo , Sepse/mortalidade , Sepse/patologia , Animais , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Bovinos , Linhagem Celular Transformada , Modelos Animais de Doenças , Endotélio/efeitos dos fármacos , Endotélio/patologia , Endotélio/ultraestrutura , Escherichia coli/fisiologia , Líquido Extracelular/efeitos dos fármacos , Citometria de Fluxo , Hemorragia/etiologia , Hemorragia/patologia , Histonas/efeitos dos fármacos , Histonas/imunologia , Histonas/farmacologia , Nefropatias/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/ultraestrutura , Camundongos , Microscopia Eletrônica de Transmissão/métodos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Papio , Polissacarídeos/efeitos adversos , Sepse/tratamento farmacológico , Sepse/etiologia , Fator de Necrose Tumoral alfa/efeitos adversos
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