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Sustainable manufacturing that prioritizes energy efficiency, minimal water use, scalability and the ability to generate diverse materials is essential to advance inorganic materials production while maintaining environmental consciousness. However, current manufacturing practices are not yet equipped to fully meet these requirements. Here we describe a flash-within-flash Joule heating (FWF) technique-a non-equilibrium, ultrafast heat conduction method-to prepare ten transition metal dichalcogenides, three group XIV dichalcogenides and nine non-transition metal dichalcogenide materials, each in under 5 s while in ambient conditions. FWF achieves enormous advantages in facile gram scalability and in sustainable manufacturing criteria when compared with other synthesis methods. Also, FWF allows the production of phase-selective and single-crystalline bulk powders, a phenomenon rarely observed by any other synthesis method. Furthermore, FWF MoSe2 outperformed commercially available MoSe2 in tribology, showcasing the quality of FWF materials. The capability for atom substitution and doping further highlights the versatility of FWF as a general bulk inorganic materials synthesis protocol.
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Superhydrophobic surfaces have gained sustained attention because of their extensive applications in the fields of self-cleaning, anti-icing, and drag reduction systems. Water droplets must have large apparent contact angle (CA) (>150°) and small CA hysteresis (<10°) on these surfaces. However, previous research usually involves complex fabrication strategies to modify the surface wettability. It is also challenging to maintain the temporal and mechanical stability of the delicate surface textures. Here, we develop a one-step solvent-free sand-in method to fabricate robust superhydrophobic surfaces directly atop various substrates with an apparent CA up to â¼163.8° and hysteresis less than 5°. The water repellency can withstand 100 Scotch tape peeling tests and remain stable after being stored under ambient humid conditions in Houston, Texas, for 18 months or being heated at 130 °C in air for 24 h. The superhydrophobic surfaces have excellent anti-icing ability, including a â¼2.6× longer water freezing time and â¼40% smaller ice adhesion strength with the temperature as low as -35 °C. Since the surface layers are fabricated by sanding the substrates with the powder additives, the surface damage can be repaired by a direct re-sanding treatment with the same powder additives. Further sand-in condition screenings broaden surface wettability from hydrophilic to superhydrophobic. The sand-in method induces the surface modification and the formation of the tribofilm. Surface and materials characterizations reveal that both microstructures and nanoscale asperities of the tribofilms contribute to the robust superhydrophobic features of sanded surfaces.
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Background: Exercise is important in type 2 diabetes (T2D) management. Focussing on Maori and Pacific people and those from deprived circumstances, the Diabetes Community Exercise Programme (DCEP) was developed to engage people with T2D in exercise. We report the evaluation of whether being offered DCEP (plus usual care) was more effective than usual care in improving glycaemic control at 1-year. Methods: A randomised, two-arm, parallel, open-label trial with blinding of outcome assessor and data analyst. Adults (age ≥35 years) with T2D recruited from two New Zealand (NZ) communities were randomised, using opaque sealed envelopes and stratified by centre with random block lengths, to DCEP or usual care. DCEP comprises twice-weekly, two-hour sessions of exercise and education over 12-weeks, followed by a twice-weekly maintenance exercise class. The primary outcome was between-group differences in mean changes of glycated haemoglobin (HbA1c) from baseline to 1-year follow-up with intention-to treat analysis. This trial is registered with the Australian NZ Clinical Trials Registry (ANZCTR): ACTRN12617001624370p and is closed to new participants. Findings: From 2018 - 2019, of 294 people screened, 165 (mean age 63·8, SD16·2 years, 56% female, 78·5% European, 14% Maori, 6% Pacific, 27% most deprived) were baseline evaluated, randomised, and analysed at study end (DCEP = 83, control = 82). Multimorbidity (≥2) and polypharmacy (>5 medications) were high (82%, 69%). We found no statistically significant between-groups differences in HbA1c (mmol/mol) change at 15 months (mean 3% higher in DCEP, 95% CI 2% lower to 8% higher, p = 0·23). Twelve-week intervention adherence was good (41% attended >80% available sessions). No adverse events were reported. Interpretation: DCEP was not effective in improving glycaemic control, possibly due to insufficient exercise intensity. Our attendance demonstrated DCEP's cultural accessibility. DCEP might be good to engage in exercise marginalised people with high Hb1Ac levels, multimorbidity, and high polypharmacy. Funding: Health Research Council of New Zealand.
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On 17 August 2017, Swope Supernova Survey 2017a (SSS17a) was discovered as the optical counterpart of the binary neutron star gravitational wave event GW170817. We report time-series spectroscopy of SSS17a from 11.75 hours until 8.5 days after the merger. Over the first hour of observations, the ejecta rapidly expanded and cooled. Applying blackbody fits to the spectra, we measured the photosphere cooling from [Formula: see text] to [Formula: see text] kelvin, and determined a photospheric velocity of roughly 30% of the speed of light. The spectra of SSS17a began displaying broad features after 1.46 days and evolved qualitatively over each subsequent day, with distinct blue (early-time) and red (late-time) components. The late-time component is consistent with theoretical models of r-process-enriched neutron star ejecta, whereas the blue component requires high-velocity, lanthanide-free material.
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On 17 August 2017, gravitational waves (GWs) were detected from a binary neutron star merger, GW170817, along with a coincident short gamma-ray burst, GRB 170817A. An optical transient source, Swope Supernova Survey 17a (SSS17a), was subsequently identified as the counterpart of this event. We present ultraviolet, optical, and infrared light curves of SSS17a extending from 10.9 hours to 18 days postmerger. We constrain the radioactively powered transient resulting from the ejection of neutron-rich material. The fast rise of the light curves, subsequent decay, and rapid color evolution are consistent with multiple ejecta components of differing lanthanide abundance. The late-time light curve indicates that SSS17a produced at least ~0.05 solar masses of heavy elements, demonstrating that neutron star mergers play a role in rapid neutron capture (r-process) nucleosynthesis in the universe.
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Several lines of evidence suggest aberrant immune response in schizophrenia, including elevated levels of cytokines. These cytokines are thought to be produced by activated microglia, the innate immune cells of the central nervous system. However, increase in translocator protein 18 kDa (TSPO), a marker of activated glia, has not been found in patients with chronic schizophrenia using second-generation radiotracers and positron emission tomography (PET)-based neuroimaging. In this study we focused on patients with recent onset of schizophrenia (within 5 years of diagnosis). Quantified levels of TSPO in the cortical and subcortical brain regions using the PET-based radiotracer [(11)C]DPA-713 were compared between the patients and healthy controls. Markers of inflammation, including interleukin 6 (IL-6), were assessed in the plasma and cerebrospinal fluid (CSF) in these participants. We observed no significant change in the binding of [(11)C]DPA-713 to TSPO in 12 patients with recent onset of schizophrenia compared with 14 controls. Nevertheless, the patients with recent onset of schizophrenia showed a significant increase in IL-6 in both plasma (P<0.001) and CSF (P=0.02). The CSF levels of IL-6 were significantly correlated with the levels of IL-6 in plasma within the total study population (P<0.001) and in patients with recent onset of schizophrenia alone (P=0.03). Our results suggest that increased levels of IL-6 may occur in the absence of changed TSPO PET signal in the brains of medicated patients with recent onset of schizophrenia. Future development of PET-based radiotracers targeting alternative markers of glial activation and immune response may be needed to capture the inflammatory signature present in the brains of patients with early-stage disease.
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Encéfalo/metabolismo , Inflamação/sangue , Inflamação/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Esquizofrenia/sangue , Esquizofrenia/líquido cefalorraquidiano , Acetamidas , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Feminino , Humanos , Inflamação/diagnóstico por imagem , Masculino , Pirazóis , Pirimidinas , Esquizofrenia/diagnóstico por imagem , Adulto JovemRESUMO
The response of individual cells at the micro-scale in cell mechanics is important in understanding how they are affected by changing environments. To control cell stresses, microfluidics can be implemented since there is tremendous control over the geometry of the devices. Designing microfluidic devices to induce and manipulate stress levels on biological cells can be aided by computational modeling approaches. Such approaches serve as an efficient precursor to fabricating various microfluidic geometries that induce predictable levels of stress on biological cells, based on their mechanical properties. Here, a three-dimensional, multiphase computational fluid dynamics (CFD) modeling approach was implemented for soft biological materials. The computational model incorporates the physics of the particle dynamics, fluid dynamics and solid mechanics, which allows us to study how stresses affect the cells. By using an Eulerian-Lagrangian approach to treat the fluid domain as a continuum in the microfluidics, we are conducting studies of the cells' movement and the stresses applied to the cell. As a result of our studies, we were able to determine that a channel with periodically alternating columns of obstacles was capable of stressing cells at the highest rate, and that microfluidic systems can be engineered to impose heterogenous cell stresses through geometric configuring. We found that when using controlled geometries of the microfluidics channels with staggered obstructions, we could increase the maximum cell stress by nearly 200 times over cells flowing through microfluidic channels with no obstructions. Incorporating computational modeling in the design of microfluidic configurations for controllable cell stressing could help in the design of microfludic devices for stressing cells such as cell homogenizers.
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Técnicas Analíticas Microfluídicas , Modelos TeóricosRESUMO
We present measurements of the thermal conductance of self-assembled monolayer (SAM) junctions formed between metal leads (Au, Ag, Pt, and Pd) with mismatched phonon spectra. The thermal conductance obtained from frequency domain thermoreflectance experiments is 65 ± 7 MW/m(2) K for matched Au-alkanedithiol-Au junctions, while the mismatched Au-alkanedithiol-Pd junctions yield a thermal conductance of 36 ± 3 MW/m(2) K. The experimental observation that junction thermal conductance (per molecule) decreases as the mismatch between the lead vibrational spectra increases, paired with results from molecular dynamics (MD) simulations, suggest that phonons scatter elastically at the metal-SAM interfaces. Furthermore, we resolve a known discrepancy between measurements and MD predictions of SAM thermal conductance by using a contact mechanics model to predict 54 ± 15% areal contact in the Au-alkanedithiol-Au experimental junction. This incomplete contact obscures the actual junction thermal conductance of 115 ± 22 MW/m(2) K, which is comparable to that of metal-dielectric interfaces.
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Aberrant function of glutamatergic pathways is likely to underlie the pathology of schizophrenia. Evidence of oxidative stress in the disease pathology has also been reported. N-Acetylaspartate (NAA) is metabolically linked to both cascades and may be a key marker in exploring the interconnection of glutamatergic pathways and oxidative stress. Several studies have reported positive correlation between the levels of NAA and Glx (the sum of glutamate and glutamine) in several brain regions in healthy subjects, by using proton magnetic resonance spectroscopy ([(1)H]MRS). Interestingly, one research group recently reported decoupling of the relationship between NAA and Glx in the hippocampus of patients with schizophrenia. Here we report levels of NAA and Glx measured using [(1)H]MRS, relative to the level of creatine (Cr) as an internal control. The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in 25 patients with schizophrenia and 17 matched healthy controls were studied. In DLPFC, NAA/Cr and Glx/Cr were significantly positively correlated in healthy controls after correction for the effect of age and smoking status and after correction for multiple comparisons (r= 0.627, P= 0.017). However, in patients with schizophrenia, the positive correlation between NAA/Cr and Glx/Cr was not observed even after correcting for these two variables (r= -0.330, P= 0.124). Positive correlation between NAA/Cr and Glx/Cr was not observed in the ACC in both groups. Decoupling of NAA and Glx in the DLPFC may reflect the interconnection of glutamatergic pathways and oxidative stress in the pathology of schizophrenia, and may possibly be a biomarker of the disease.
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Ácido Aspártico/análogos & derivados , Ácido Glutâmico/metabolismo , Giro do Cíngulo/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismo , Adulto , Ácido Aspártico/metabolismo , Estudos de Casos e Controles , Creatina/metabolismo , Feminino , Glutamina/metabolismo , Giro do Cíngulo/patologia , Humanos , Masculino , Testes Neuropsicológicos , Estresse Oxidativo , Córtex Pré-Frontal/patologia , Espectroscopia de Prótons por Ressonância Magnética , Esquizofrenia/patologiaRESUMO
Rilpivirine long-acting (RPV-LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple-compartment pharmacokinetics (PK) after a single dose, for pre-exposure prophylaxis. Sixty-six HIV-negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervicovaginal lavage (CVL) was also assessed. After a single dose, RPV concentrations peaked at days 6-8 and were present in plasma and genital-tract fluid to day 84. Vaginal and male rectal tissue levels matched those in plasma. At the 1,200 mg dose, CVL showed greater antiviral activity, above baseline, at days 28 and 56. All doses were well tolerated. All doses gave prolonged plasma and genital-tract rilpivirine exposure. PK and viral inhibition of repeated doses will be important in further dose selection.
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Fármacos Anti-HIV/farmacocinética , Soronegatividade para HIV , Modelos Biológicos , Nitrilas/farmacocinética , Pirimidinas/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Química Farmacêutica , Relação Dose-Resposta a Droga , Feminino , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Injeções Intramusculares , Londres , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Nitrilas/sangue , Estudos Prospectivos , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Reto/metabolismo , Rilpivirina , Vagina/metabolismo , Adulto JovemRESUMO
Modern management of leukemia and selection of optimal treatment approaches entails the analysis of multiple recurrent cytogenetic abnormalities with independent diagnostic or prognostic value. We report the first multicenter validation of a multiplex molecular assay for 12 relevant fusion transcripts relative to cytogenetic methods. Performance was evaluated using a set of 280 adult and pediatric acute or chronic leukemias representative of the variety of presentations and pre-analytical parameters encountered in the clinical setting. The positive, negative and overall agreements were >98.5% with high concordance at each of the four sites. Positive detection of cases with low blast count or at relapse was consistent with a method sensitivity of 1%. There was 98.7% qualitative agreement with independent reference molecular tests. Apparent false negatives corresponded to rare alternative splicing isoforms not included in the panel. We further demonstrate that clinical sensitivity can be increased by adding those rare variants and other relevant transcripts or submicroscopic abnormalities. We conclude that multiplex RT-PCR followed by liquid bead array detection is a rapid and flexible method attuned to the clinical laboratory workflow, complementing standard cytogenetic methods and generating additional information valuable for the accurate diagnosis, prognosis and subsequent molecular monitoring of leukemia.
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As the industrial community moves towards green manufacturing processes, there is an increased demand for multi-functional, environmentally friendly lubricants with enhanced tribological performance. In the present investigation, green (environmentally benign) lubricant combinations were prepared by homogeneously mixing nano- (20 nm), sub-micrometre- (600 nm average size) and micrometre-scale (4 µm average size) boric acid powder additives with canola oil in a vortex generator. As a basis for comparison, lubricants of base canola oil and canola oil mixed with MoS(2) powder (ranging from 0.5 to 10 µm) were also prepared. Friction and wear experiments were carried out on the prepared lubricants using a pin-on-disc apparatus under ambient conditions. Based on the experiments, the nanoscale (20 nm) particle boric acid additive lubricants significantly outperformed all of the other lubricants with respect to frictional and wear performance. In fact, the nanoscale boric acid powder-based lubricants exhibited a wear rate more than an order of magnitude lower than the MoS(2) and larger sized boric acid additive-based lubricants. It was also discovered that the oil mixed with a combination of sub-micrometre- and micrometre-scale boric acid powder additives exhibited better friction and wear performance than the canola oil mixed with sub-micrometre- or micrometre-scale boric acid additives alone.
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The study of granular flows in physics has always been important because of their recurring presence in nature and industry. However, the nonlinear and multiphase behavior exhibited by these particulate systems makes them hard to model and predict. Several experiments were conducted in the past to gain insight into granular flows. The current experimental work furthers this insight and specifically attempts to understand the effect of rough surfaces on granular flows, namely, their local flow behavior. Understanding this interaction can have implications on industrial-scale granular problems. In this work, a granular shear cell, a two-dimensional annular shear cell, was developed to conduct shear experiments where roughness is imposed on the driving surface and experimentally quantified. A digital particle tracking velocimetry data retrieval scheme was developed to extract solid fraction, velocity, and granular temperature data from the experiments as a function of the roughness factor and wheel rotation rate. In general, the steady-state results show the two distinct regions as expected-a high-velocity and dilute-gas-like kinetic region near the moving wall and a high-solid-fraction liquid-like frictional flow regime away from the moving wall. Parametric studies conducted show that the normalized slip near the moving wall decreases with increasing wall roughness and decreasing wall rotation rate. Slip is an important parameter which can be easily interpreted as momentum transfer or traction performance in granular systems related to wheel-terrain interaction, agricultural processing, and most notably granular lubrication.
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Building upon our initial studies in young adult surgically menopausal monkeys, this study examined the effects of a novel schedule of administration of estradiol therapy alone, or in combination with progesterone, on visual and spatial recognition memory in older monkeys. Monkeys were preoperatively trained on a delayed matching-to-sample task and a delayed response task. At the time of ovariectomy, monkeys began their hormonal treatments and were cognitively assessed at 2, 12 and 24 weeks following treatment initiation. A schedule of hormone administration was used that closely modeled the normal fluctuations of hormones during the course of a normal primate menstrual cycle. Monkeys receiving placebo had lower levels of accuracy than monkeys receiving estrogen therapies on the delayed matching-to-sample task that were not apparent until 12 weeks following initiation of therapy and were no longer detected at the 24-week assessment. There was no effect of hormone therapy on accuracy in the delayed response task at any of the postoperative assessments. In both tasks, monkeys treated with estrogen plus progesterone had longer choice response latencies, especially on trials in which they made errors; however these effects did not influence accuracy measures in these animals. Our findings indicate that visual recognition ability may be more sensitive than spatial recognition memory to this novel hormone therapy regimen, that treatment with estradiol plus progesterone was equivalent to that of estradiol alone, and that neither therapy had significant negative impact on memory profiles.
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Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Memória/efeitos dos fármacos , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Animais , Terapia de Reposição de Estrogênios , Feminino , Macaca mulatta , Menopausa , Ovariectomia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacosRESUMO
Sixty-six patients with cancer-related pain entered an open multicentre study to examine the safety and efficacy of oral transmucosal fentanyl citrate (OTFC) in the treatment of breakthrough pain. Patients were eligible for the study if they were stabilized on a long-acting opioid but were experiencing up to four episodes of breakthrough pain a day and achieving at least partial relief from breakthrough pain using conventional medication (normal release oral morphine in the majority of patients). The efficacy of the conventional medication was documented in a run-in phase and patients then changed to OTFC. All patients were treated initially with a 200 mcg unit of OTFC and the dose was increased if necessary to a level that produced relief of breakthrough pain without troublesome adverse effects. Fifty-eight patients completed the run-in phase using their usual medication and entered the dose titration phase with OTFC and 57 patients received at least one dose of OTFC. Forty-two patients (72%) found a successful dose of OTFC. The primary outcome measures were the Summed Pain Intensity Differences (SPID) and Total Pain Relief (TOTPAR) scores at 60 min. There was a significant difference in both measures in favour of OTFC compared with conventional medication in these patients. Twenty-eight of the 42 patients (67%) preferred OTFC to their usual medication. The most common adverse effects attributed to OTFC were nausea, stomatitis, vomiting and dizziness but there were no unpredicted or severe problems. Thirty-seven patients continued into the long-term study and 12 of these completed six months treatment. Most drop-outs in this phase were associated with progression of the underlying disease. No patient stopped using OTFC because of dissatisfaction with the drug. OTFC appears to be a safe and effective treatment for breakthrough pain in cancer patients and may have advantages over currently available opioid formulations.
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Analgésicos Opioides/administração & dosagem , Fentanila/administração & dosagem , Neoplasias/complicações , Dor Intratável/prevenção & controle , Administração Bucal , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/efeitos adversos , Feminino , Fentanila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Dor Intratável/etiologia , Resultado do TratamentoRESUMO
AIMS: To evaluate the potential pharmacokinetic interaction between the HIV protease inhibitor saquinavir and rifabutin. METHODS: Fourteen HIV-infected patients provided full steady-state pharmacokinetic profiles following administration of rifabutin alone (300 mg once daily) or saquinavir soft-gel formulation (1200 mg three times daily) plus rifabutin (300 mg once daily) in this open label, partially randomized study. RESULTS: Coadministration of saquinavir and rifabutin resulted in a reduction in saquinavir AUC(0,8 h) and C(max)(0,8 h) of 47% (95% CI 30, 60%) and 39% (95% CI 11, 59%), respectively. Rifabutin AUC(0,24 h) and C(max)(0,24 h) was increased by an average of 44% (95% CI 17, 78%) and 45% (95% CI 14, 85%), respectively. Saquinavir in combination with rifabutin was well tolerated. Gastrointestinal intolerance and asymptomatic increases in liver enzymes were the only adverse events of note. CONCLUSIONS: Administration of rifabutin with saquinavir may decrease the efficacy of this HIV protease inhibitor.
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Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Rifabutina/farmacocinética , Saquinavir/farmacocinética , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Rifabutina/uso terapêutico , Saquinavir/uso terapêuticoRESUMO
OBJECTIVES: To evaluate the impact of an information booklet on HIV clinical trials, Clinical Trials in HIV and AIDS: Information For People Who Are Thinking About Joining a Trial, in addition to the standard trial information (SI) on patients' knowledge; understanding and attitudes about clinical trials; and to investigate patients' motivations and reasons for enrolling or not enrolling in a clinical trial. METHODS: Fifty HIV-1 positive patients who attended the HIV clinic at a west London hospital were randomized to receive either SI alone (n = 27) or SI and a 16 page information booklet explaining the principles and procedures of HIV clinical trials (n = 23). A self-administered questionnaire was used at baseline to assess past experience and attitudes to clinical trials (10 questions), knowledge and understanding of HIV treatments (8 questions) and clinical trials (11 questions). At 2-6 months after randomization, a second interviewer-administered questionnaire addressed the patient's assessment of the usefulness and comprehensiveness of the information provided by the SI and information booklet, whether or not the patient had enrolled in a clinical trial and reasons for enrolling/not enrolling, knowledge of specific aspects of the trial protocol the patient was eligible to join (13 questions) and general knowledge of clinical trial procedures (repeat of 11 baseline questions). Changes in the attitudes and scores on knowledge and understanding of clinical trials were compared for the two groups. RESULTS: In both groups, patient knowledge of clinical trial procedures improved significantly over the study period. The median score increased from 30 at baseline to 35/44 at follow-up (SI only) vs. 24-31/44 (SI plus booklet), but this did not differ significantly between the two groups. However, knowledge of the specific trial protocol was poor [median score 13/25, interquartile range (IQR) 8-14], and there was no difference in the scores for the two groups. The prime motivations for joining a clinical trial were to benefit personal health and to gain access to new treatments. Potential side-effects were the main concern of prospective trial participants. CONCLUSIONS: This small trial shows that, while the patients' general knowledge and understanding of clinical trials improved over time, this was not improved by the information booklet and recollection of the details of the relevant trial protocol remained poor.
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Fármacos Anti-HIV/uso terapêutico , Ensaios Clínicos como Assunto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Folhetos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Educação de Pacientes como Assunto/métodos , Seleção de Pacientes , Materiais de Ensino/normas , Adulto , Fármacos Anti-HIV/efeitos adversos , Escolaridade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
The evolutionary trace (ET) method, a data mining approach for determining significant levels of amino acid conservation, has been applied to over 700 aligned G-protein-coupled receptor (GPCR) sequences. The method predicted the occurrence of functionally important clusters of residues on the external faces of helices 5 and 6 for each family or subfamily of receptors; similar clusters were observed on helices 2 and 3. The probability that these clusters are not random was determined using Monte Carlo techniques. The cluster on helices 5 and 6 is consistent with both 5,6-contact and 5,6-domain swapped dimer formation; the possible equivalence of these two types of dimer is discussed because this relates to activation by homo- and heterodimers. The observation of a functionally important cluster of residues on helices 2 and 3 is novel, and some possible interpretations are given, including heterodimerization and oligomerization. The application of the evolutionary trace method to 113 aligned G-protein sequences resulted in the identification of two functional sites. One large, well-defined site is clearly identified with adenyl cyclase, beta/gamma and regulator of G-protein signaling (RGS) binding. The other G-protein functional site, which extends from the ras-like domain onto the helical domain, has the correct size and electrostatic properties for GPCR dimer binding. The implications of these results are discussed in terms of the conformational changes required in the G-protein for activation by a receptor dimer. Further, the implications of GPCR dimerization for medicinal chemistry are discussed in the context of these ET results.
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Proteínas de Ligação ao GTP/química , Receptores de Superfície Celular/química , Sequência de Aminoácidos , Sequência Consenso , Dimerização , Modelos Moleculares , Método de Monte Carlo , Mutação , Receptores de Superfície Celular/genéticaRESUMO
In recent years there has been an increasing number of reports describing G protein-coupled receptor (GPCR) dimerization and heterodimerization. However, the evidence on the nature of the dimers and their role in GPCR activation is inconclusive. Consequently, we present here a review of our computational studies on G protein-coupled receptor dimerization and domain swapping. The studies described include molecular dynamics simulations on receptor monomers and dimers in the absence of ligand, in the presence of an agonist, and in the presence of an antagonist (or more precisely an inverse agonist). Two distinct sequence-based approaches to studying protein interfaces are also described, namely correlated mutation analysis and evolutionary trace analysis. All three approaches concur in supporting the proposal that the dimerization interface includes transmembrane helices 5 and 6. These studies cannot distinguish between domain swapped dimers and contact dimers as the models used were restricted to the helical part of the receptor. However, it is proposed that for the purpose of signalling, the domain swapped dimer and the corresponding contact dimer are equivalent. The evolutionary trace analysis suggests that every GPCR family and subfamily (for which sufficient sequence data is available) has the potential to dimerize through this common functional site on helices 5 and 6. The evolutionary trace results on the G protein are briefly described and these are consistent with GPCR dimerization. In addition to the functional site on helices 5 and 6, the evolutionary trace analysis identified a second functional site on helices 2 and 3. Possible roles for this site are suggested, including oligomerization.
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Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/metabolismo , Estrutura Terciária de Proteína/fisiologia , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Animais , Sítios de Ligação/fisiologia , Análise Mutacional de DNA/métodos , Dimerização , Evolução Molecular , Sequências Hélice-Alça-Hélice/fisiologia , Humanos , Receptores de GABA-B/química , Receptores de GABA-B/metabolismoRESUMO
Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.