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1.
Physiol Rep ; 8(10): e14448, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32441493

RESUMO

Hypertension plays an important role in the development and progression of chronic kidney disease. Studies to date, with mineralocorticoid receptor antagonists (MRA), have demonstrated varying degrees of results in modifying the development of renal fibrosis. This study aimed to investigate whether treatment with a MRA commenced following the establishment of hypertension, a situation more accurately representing the clinical setting, modified the progression of renal fibrosis. Using male Cyp1a1Ren2 rats (n = 28), hypertension was established by addition of 0.167% indole-3-carbinol (w/w) to the rat chow, for 2 weeks prior to treatment. Rats were then divided into normotensive, hypertensive (H), or hypertensive with daily oral spironolactone treatment (H + SP) (human equivalent dose 50 mg/day). Physiological data and tissue were collected after 4 and 12 weeks for analysis. After 4 weeks, spironolactone had no demonstrable effect on systolic blood pressure (SBP), proteinuria, or macrophage infiltration in the renal cortex. However, glomerulosclerosis and renal cortical fibrosis were significantly decreased. Following 12 weeks of spironolactone treatment, SBP was lowered (not back to normotensive levels), proteinuria was reduced, and the progression of glomerulosclerosis and renal cortical fibrosis was significantly blunted. This was associated with a significant reduction in macrophage and myofibroblast infiltration, as well as CTGF and pSMAD2 expression. In summary, in a model of established hypertension, spironolactone significantly blunted the progression of renal fibrosis and glomerulosclerosis, and downregulated the renal inflammatory response, which was associated with reduced proteinuria, despite only a partial reduction in systolic blood pressure. This suggests a blood pressure independent effect of MRA on renal fibrosis.

2.
Phys Chem Chem Phys ; 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32337517

RESUMO

Operando Raman spectroscopy and electrochemical techniques were used to examine carbon deposition on niobium doped SrTiO3 (STN) based SOFC anodes infiltrated with Ni, Co, Ce0.9Gd0.1O2 (CGO) and combinations of these materials. Cells were operated with CH4/CO2 mixtures at 750 °C. Raman data shows that carbon forms on all cells under operating conditions when Ni is present as an infiltrate. Additional experiments performed during cell cool down, and on separate material pellets (not subject to an applied potential), show that chemically labile oxygen available in the CGO infiltrate will preferentially oxidize all deposited surface carbon as temperatures drop below 700 °C. These observations highlight the benefit of CGO as a material in SOFC anodes but more importantly, the value of operando spectroscopic techniques as a tool when evaluating a material's susceptibility to carbon accumulation. Solely relying on ex situ measurements will potentially lead to false conclusions about the studied materials' ability to resist carbon and improperly inform efforts to develop mechanisms describing electrochemical oxidation and material degradation mechanisms in these high temperature energy conversion devices.

3.
Physiol Meas ; 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32272458

RESUMO

OBJECTIVE: To test the reliability of immediate replication of muscle cramp characteristics induced with different electrical stimulation protocols. APPROACH: Five (age 33.8 ± 5.7 y, 60% male) and ten (age 47.4 ± 11.7 y, 60% male) participants completed independent discovery and validation cohorts, respectively. This was to identify a protocol that resulted in consistent muscle cramp characteristics (discovery), and to examine the test-retest reliability of the identified protocol (validation). Electrical stimulation (150 burst) at abductor hallucis motor-point was used to induce muscle cramps with 4 Hz increments in stimulation frequency (8 to 32 Hz) or until muscle cramp was first evident, followed by refinement (2 and 1 Hz) until at least two muscle cramps occurred. This defined the cramp threshold frequency, and concurrent electromyogram activity and duration of the cramp were quantified. The discovery cohort involved three separate randomised sessions where intervals between stimulation was 60, 90, and 120 s respectively. In each session, four randomised electrical stimulation protocols were completed. Stimulation current was fixed at 10, 20, and 30% higher than m-wave stimulation current (protocols 1-3 respectively), or randomised within 4 Hz steps (protocol 4) to minimise any order effect. MAIN RESULTS: We were able to immediately replicate tolerable muscle cramp at least twice. Discovery cohort demonstrated (i) incremental changes in stimulation frequency (protocols 1 - 3 vs. protocol 4; i.e., order effect), and (ii) changes in stimulation current with differing protocols did not significantly alter the prevailing muscle cramp characteristics, and (iii) defining the muscle cramp characteristics elicits good-to-excellent inter-observer reliability. The validation cohort's test-retest reliability and the minimum detectable change were improved for all muscle cramp characteristics when immediately replicated more than twice at the lowest stimulation frequency. SIGNIFICANCE: This study provides evidence for a reliable method for inducing repeatable muscle cramps in abductor hallucis.

4.
Psychiatr Rehabil J ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32191104

RESUMO

OBJECTIVE: The primary purpose of the study was to evaluate the psychometric properties of the Job Satisfaction of Persons with Disabilities Scale in a sample of peer support specialists. METHOD: A total of 121 employed peer support specialists with lived experience of a serious mental health condition were recruited for this study from statewide peer certification training programs and the International Association of Peer Supporters. Respondents completed an online survey on job satisfaction and related constructs. A principal components analysis was used to explore and identify the instrument subscales. RESULTS: The findings identified 2 factors: (a) the 9-item job satisfaction with intangible benefits factor and (b) the 5-item job satisfaction with tangible benefits factor. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The Job Satisfaction of Persons with Disabilities Scale demonstrates good-to-excellent psychometrics. The use of this scale among peer support specialists within training and supervision practices in psychiatric rehabilitation settings is warranted. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

5.
Genetics ; 214(4): 839-854, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32111629

RESUMO

Centromeric localization of CENP-A (Cse4 in Saccharomyces cerevisiae, CID in flies, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of overexpressed CENP-A contributes to aneuploidy in yeast, flies, and humans, and is proposed to promote tumorigenesis in human cancers. Hence, defining molecular mechanisms that promote or prevent mislocalization of CENP-A is an area of active investigation. In budding yeast, evolutionarily conserved histone chaperones Scm3 and chromatin assembly factor-1 (CAF-1) promote localization of Cse4 to centromeric and noncentromeric regions, respectively. Ubiquitin ligases, such as Psh1 and Slx5, and histone chaperones (HIR complex) regulate proteolysis of overexpressed Cse4 and prevent its mislocalization to noncentromeric regions. In this study, we have identified sumoylation sites lysine (K) 215/216 in the C terminus of Cse4, and shown that sumoylation of Cse4 K215/216 facilitates its genome-wide deposition into chromatin when overexpressed. Our results showed reduced levels of sumoylation of mutant Cse4 K215/216R/A [K changed to arginine (R) or alanine (A)] and reduced interaction of mutant Cse4 K215/216R/A with Scm3 and CAF-1 when compared to wild-type Cse4 Consistent with these results, levels of Cse4 K215/216R/A in the chromatin fraction and localization to centromeric and noncentromeric regions were reduced. Furthermore, in contrast to GAL- CSE4, which exhibits Synthetic Dosage Lethality (SDL) in psh1∆, slx5∆, and hir2∆ strains, GAL- cse4 K215/216R does not exhibit SDL in these strains. Taken together, our results show that deposition of Cse4 into chromatin is facilitated by its C-terminal sumoylation.

6.
PLoS Genet ; 16(2): e1008597, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32032354

RESUMO

Restricting the localization of the histone H3 variant CENP-A (Cse4 in yeast, CID in flies) to centromeres is essential for faithful chromosome segregation. Mislocalization of CENP-A leads to chromosomal instability (CIN) in yeast, fly and human cells. Overexpression and mislocalization of CENP-A has been observed in many cancers and this correlates with increased invasiveness and poor prognosis. Yet genes that regulate CENP-A levels and localization under physiological conditions have not been defined. In this study we used a genome-wide genetic screen to identify essential genes required for Cse4 homeostasis to prevent its mislocalization for chromosomal stability. We show that two Skp, Cullin, F-box (SCF) ubiquitin ligases with the evolutionarily conserved F-box proteins Met30 and Cdc4 interact and cooperatively regulate proteolysis of endogenous Cse4 and prevent its mislocalization for faithful chromosome segregation under physiological conditions. The interaction of Met30 with Cdc4 is independent of the D domain, which is essential for their homodimerization and ubiquitination of other substrates. The requirement for both Cdc4 and Met30 for ubiquitination is specifc for Cse4; and a common substrate for Cdc4 and Met30 has not previously been described. Met30 is necessary for the interaction between Cdc4 and Cse4, and defects in this interaction lead to stabilization and mislocalization of Cse4, which in turn contributes to CIN. We provide the first direct link between Cse4 mislocalization to defects in kinetochore structure and show that SCF-mediated proteolysis of Cse4 is a major mechanism that prevents stable maintenance of Cse4 at non-centromeric regions, thus ensuring faithful chromosome segregation. In summary, we have identified essential pathways that regulate cellular levels of endogenous Cse4 and shown that proteolysis of Cse4 by SCF-Met30/Cdc4 prevents mislocalization and CIN in unperturbed cells.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Instabilidade Cromossômica , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas F-Box/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Complexos Ubiquitina-Proteína Ligase/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Centrômero/metabolismo , Segregação de Cromossomos , Domínios Proteicos , Proteólise , Ubiquitinação
7.
Orthopedics ; 43(3): 187-190, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32077966

RESUMO

Understanding trends in reimbursement for orthopedic surgery is important, especially considering the changing landscape of health care delivery and payment models. Although other studies have examined these trends using a sampling of common orthopedic procedures compared with non-orthopedic specialties, robust examination across all orthopedic specialties is not available in the current literature. This study aimed to critically analyze the trends in reimbursement in the field of orthopedic surgery. Inflation-adjusted Medicare reimbursement and work relative value units (RVUs) between 2000 and 2016 for more than 200 individual Current Procedural Terminology codes across all major orthopedic subspecialties were analyzed, and inherent value of work RVUs was assessed by dividing reimbursement dollar values by work RVUs annually and tracking the changes. Between 2000 and 2016, reimbursement decreased across all orthopedic subspecialties by an average of 29%, except oncology, which showed a 6% increase. Work RVUs increased by an average of 10%, but the inherent value of work RVUs decreased across all orthopedic subspecialties by an average of 39%. Increased active involvement of orthopedic attending physicians and residents in coding documentation and fee-schedule representation is needed. [Orthopedics. 2020;43(3):187-190.].

8.
J Am Chem Soc ; 142(5): 2375-2385, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31937100

RESUMO

Time-resolved fluorescence emission and resonance-enhanced second harmonic generation (SHG) spectra were collected from 4-dimethylaminobenzonitrile (DMABN) adsorbed to the aqueous-silica interface in order to identify how strongly associating solvent-substrate interactions change DMABN's photoisomerization properties. In bulk polar solution, DMABN forms an excited twisted intramolecular charge-transfer (TICT) state that emits with a distinctive, solvatochromic fluorescent signature. At the silica-aqueous interface, the TICT fluorescence disappears, similar to DMABN's behavior in nonpolar environments. SHG spectra confirm that the interface is, in fact, polar, and DMABN's unusual fluorescence emission acquired from the interface is attributed to strong hydrogen bonding associations between the water molecules and the silica surface that prevent adsorbate isomerization. Additionally, SHG spectra show a strong resonance at long wavelengths that is unexpected based on bulk absorbance spectra and selection rules for nonlinear hyperpolarizabilities. Using both Zerner's INDO semiempirical and TD-DFT calculations, this spectroscopic behavior is attributed to a combination of strong electric fields present at the aqueous-silica interface and surface-induced changes to DMABN's ground-state molecular structure.

9.
J Orthop Trauma ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31977668

RESUMO

BACKGROUND: One of the main shortcomings of current proximal humeral plate designs is their inability to reliably secure the greater (GT) or lesser (LT) tuberosities, leading to fixation failure, nonunion, and rotator cuff dysfunction. Traditional proximal humeral locking plates rely on isolated screw fixation or suture repair to maintain reduction of the greater and/or lesser tuberosities. This study evaluates a tuberosity-based plate specifically designed to improve tuberosity fixation, which may decrease tuberosity displacement and related clinical sequelae. METHODS: Five cadaveric specimens (ten shoulders) were randomized to receive either standard proximal humeral locking plate (PHLP) or tuberosity-based plate fixation (TBP). The specimens were skeletonized except for the rotator cuff insertion on the greater tuberosity. A reproducible 3-part osteotomy was performed for each cadaver, creating head, shaft, and GT segments. Anatomic reduction and plate fixation were performed according to the surgical technique guide for each plate system, with an equal number of screws placed in each plate both proximally and distally. GT fixation was enhanced with standardized suture augmentation through the rotator cuff in every specimen in both groups. In each trial, fracture displacement, load to failure, number of cycles endured, and mechanism of failure were noted. RESULTS: The mean load to tuberosity fixation failure for the PHLP and TBP groups was 220N and 502N (p=0.005), respectively. CONCLUSIONS: The TBP had a significantly higher load to failure and significantly lower mean fracture displacement compared to the PHLP. LEVEL OF EVIDENCE: N/A.

10.
PLoS One ; 15(1): e0227378, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31986157

RESUMO

Since 1984, nearly 1,000 people have been killed in the Brazilian Amazon due to land conflicts stemming from unequal distribution of land, land tenure insecurity, and lawlessness. During this same period, the region experienced almost complete deforestation (< 8% forest cover by 2010). Land conflict exacts a human toll, but it also affects agents' decisions about land use, the subject of this article. Using a property-level panel dataset covering the period of redemocratization in Brazil (1984) until the privatization of long-term leases in the Eastern Amazon (2010), we show that deforestation is affected by land conflict, particularly in cases of expropriation of property for agrarian reform settlement formation and when that conflict involves fatalities. Deforestation on agrarian reform settlements is much greater when soils are poor for agriculture and when the land has been the object of past conflict. Deforestation and conflict are episodic, and both agronomic drivers and contentious drivers of land change are active in the region. Ultimately, the outcome of these processes of contentious and agronomic land change is substantial deforestation, regardless of who was in possession and control of the land.


Assuntos
Agricultura/estatística & dados numéricos , Conservação dos Recursos Naturais/estatística & dados numéricos , Propriedade/estatística & dados numéricos , Brasil , Florestas , Humanos , Estudos Longitudinais
11.
JMIR Mhealth Uhealth ; 8(1): e14512, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31934874

RESUMO

The rapid proliferation of health informatics and digital health innovations has revolutionized clinical and research practices. There is no doubt that these fields will continue to have accelerated growth and a substantial impact on population health. However, there are legitimate concerns about how these promising technological advances can lead to unintended consequences such as perpetuating health and health care disparities for underresourced populations. To mitigate this potential pitfall, it is imperative for the health informatics and digital health scientific communities to understand the challenges faced by disadvantaged groups, including racial and ethnic minorities, which hinder their achievement of ideal health. This paper presents illustrative exemplars as case studies of contextually tailored, sociotechnical mobile health interventions designed with community members to address health inequities using community-engaged research approaches. We strongly encourage researchers and innovators to integrate community engagement into the development of data-driven, modernized solutions for every sector of society to truly achieve health equity for all.

12.
Clin Infect Dis ; 70(5): 773-779, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30944930

RESUMO

BACKGROUND: Recent reports have described the contribution of adult respiratory syncytial virus (RSV) infections to the use of advanced healthcare resources and death. METHODS: Data regarding patients aged ≥18 years admitted to any of Maryland's 50 acute-care hospitals were evaluated over 12 consecutive years (2001-2013). We examined RSV and influenza (flu) surveillance data from the US National Respiratory and Enteric Virus Surveillance System and the Centers for Disease Control and Prevention and used this information to define RSV and flu outbreak periods in the Maryland area. Outbreak periods consisted of consecutive individual weeks during which at least 10% of RSV and/or flu diagnostic tests were positive. We examined relationships of RSV and flu outbreaks to occurrence of 4 advanced medical outcomes (hospitalization, intensive care unit admission, intubated mechanical ventilation, and death) due to medically attended acute respiratory illness (MAARI). RESULTS: Occurrences of all 4 MAARI-related hospital advanced medical outcomes were consistently greater for all adult ages during RSV, flu, and combined RSV-flu outbreak periods compared to nonoutbreak periods and tended to be greatest in adults aged ≥65 years during combined RSV-flu outbreak periods. Rate ratios for all 4 MAARI-related advanced medical outcomes ranged from 1.04 to 1.38 during the RSV, flu, or combined RSV-flu outbreaks compared to the nonoutbreak periods, with all 95% lower confidence limits >1. CONCLUSIONS: Both RSV and flu outbreaks were associated with surges in MAARI-related advanced medical outcomes (hospitalization, intensive care unit admission, intubated mechanical ventilation, and death) for adults of all ages.

13.
Eur J Clin Pharmacol ; 76(2): 239-247, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31814045

RESUMO

OBJECTIVE: We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration (SLED-HDF) to inform the dosing of these drugs in an acute setting. PARTICIPANTS: Six stable patients with end-stage kidney disease. METHODS: An open-label pilot pharmacokinetic study of meropenem and piperacillin-tazobactam. SLED-HDF was undertaken for 4 h. Plasma drug concentrations were measured pre- and post-filter and in the effluent at multiple time points. The pharmacokinetic data was analysed using non-compartmental methods. The fraction of time that individual plasma concentration profiles were predicted to remain above the MIC break-points for commonly isolated gram-negative pathogens during a prolonged SLED-HDF session was assessed using two targets; fT > MIC (fraction of time above the MIC) and the more aggressive fT > 4 × MIC (fraction of time above 4 × MIC). RESULTS: Meropenem total and SLED-HDF clearance ranged from 141 to 180 mL/min and 126-205 mL/min, respectively. Piperacillin total and SLED-HDF clearance values ranged from 131 to 252 mL/min and 135-162 mL/min, respectively. Our results suggest that prolonged SLED-HDF (12 h) will only maintain a sufficient meropenem and piperacillin-tazobactam plasma concentration to achieve a target of fT > MIC for gram-negative pathogens (MIC 2 mg/L-meropenem, 8 mg/L-piperacillin-tazobactam) for less than 40% of the time. Plasma concentrations would be inadequate to achieve the more aggressive target of 100 % fT > 4xMIC target recommended for critically unwell patients. CONCLUSIONS: The pharmacokinetic data obtained from this pilot study demonstrate significant quantities of meropenem and piperacillin are removed during a SLED-HDF session. This may lead to subtherapeutic concentrations of piperacillin and meropenem over the duration of HDF session. TRIAL REGISTRATION: Australasian Clinical Trials Registry Network (ACTRN12616000078459).

14.
Sci Rep ; 9(1): 17213, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748606

RESUMO

Transgenic mice that express either a NUP98-PHF23 (NP23) or NUP98-HOXD13 (NHD13) fusion in the hematopoietic compartment develop a wide spectrum of leukemias, including myeloid, erythroid, megakaryocytic and lymphoid, at age 9-14 months. NP23-NHD13 double transgenic mice were generated by interbreeding NP23 and NHD13 mice. Remarkably, 100% of the NP23-NHD13 double transgenic mice developed acute myeloid leukemia (AML) within three months, characterized by replacement of the thymus with leukemic myeloblasts. The marked infiltration of thymus led to the intriguing hypothesis that AML generated in NP23-NHD13 mice arose in the thymus, as opposed to the bone marrow (BM). Transplantation of CD4-CD8- double negative (DN) thymocytes (which were also negative for Mac1 and Gr1) from leukemic NHD13/NP23 mice demonstrated that DN thymocytes could transmit AML, and limiting dilution studies showed that leukemia initiating cells were increased 14-fold in the thymus compared to BM. Further thymocyte fractionation demonstrated that DN1 and DN2, but not DN3 or DN4 fractions transmitted AML, and a marked expansion (100-fold) of Lineage-Sca1 + Kit + (LSK) cells in the thymus of the NP23-NHD13 mice. Taken together, these results show that the thymus of NP23-NHD13 mice acts as a reservoir for AML initiating cells and that thymic progenitors can transmit AML.

15.
N Engl J Med ; 381(24): 2293-2303, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31774950

RESUMO

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).


Assuntos
Alanina/análogos & derivados , Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Doença pelo Vírus Ebola/tratamento farmacológico , Ribonucleotídeos/uso terapêutico , Adolescente , Adulto , Alanina/efeitos adversos , Alanina/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Antivirais/efeitos adversos , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Surtos de Doenças , Ebolavirus/genética , Feminino , Doença pelo Vírus Ebola/mortalidade , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Masculino , RNA Viral/sangue , Ribonucleotídeos/efeitos adversos , Método Simples-Cego , Adulto Jovem
16.
Foods ; 8(10)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614805

RESUMO

The characteristics of plum fruits of three different species were investigated throughout their development (including over-ripening). The content of primary and secondary metabolites was expressed as amount per gram DW (dry weight) and per fruit in order to obtain information about the balance between their synthesis and dissimilation at different stages of fruit development. In all the plums, during the first stages of development, glucose was the most abundant sugar, whereas sucrose increased during ripening. There was no decrease in malate content per fruit before the commercial harvesting time of any of the plums, whereas a decrease was observed during over-ripening. In general, both the total phenol content and the contents of individual phenols in the flesh expressed on gram DW decreased throughout development, whereas their content per fruit increased, indicating that these decreases were due to a dilution effect arising from the expansion of the flesh. During the development of the flesh, the increase in the contents of the investigated metabolites per fruit shows that there was no net dissimilation of malate up to commercial harvest and of phenols throughout fruit development. Good correlations between the content of phenols to antioxidant activity were found. Shiro flesh, during the last part of fruit development, had lower total carbohydrate and polyphenol contents, lower antioxidant activities, and a higher malate content than the flesh of the other two genotypes.

18.
Can J Kidney Health Dis ; 6: 2054358119879896, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31662874

RESUMO

Background: There are limited studies on the effects of statins on outcomes in the moderate chronic kidney disease (CKD) population and their trajectory to end-stage kidney disease. Objective: To examine the long-term effects of lipid-lowering therapy on all-cause mortality, cardiovascular morbidity, CKD progression, and socioeconomic well-being in Australian, New Zealand, and Malaysian SHARP (Study of Heart and Renal Protection) trial participants-a randomized controlled trial of a combination of simvastatin and ezetimibe, compared with placebo, for the reduction of cardiovascular events in moderate to severe CKD. Design: Protocol for an extended prospective observational follow-up. Setting: Australian, New Zealand, and Malaysian participating centers in patients with advanced CKD. Patients: All SHARP trial participants alive at the final study visit. Measurements: Primary outcomes were measured by participant self-report and verified by hospital administrative data. In addition, secondary outcomes were measured using a validated study questionnaire of health-related quality of life, a 56-item economic survey. Methods: Participants were followed up with alternating face-to-face visits and telephone calls on a 6-monthly basis until 5 years following their final SHARP Study visit. In addition, there were 6-monthly follow-up telephone calls in between these visits. Data linkage to health registries in Australia, New Zealand, and Malaysia was also performed. Results: The SHARP-Extended Review (SHARP-ER) cohort comprised 1136 SHARP participants with a median of 4.6 years of follow-up. Compared with all SHARP participants who originally participated in the Australian, New Zealand, and Malaysian regions, the SHARP-ER participants were younger (57.2 [48.3-66.4] vs 60.5 [50.3-70.7] years) with a lower proportion of men (61.5% vs 62.8%). There were a lower proportion of participants with hypertension (83.7% vs 85.0%) and diabetes (20.0% vs 23.5%). Limitations: As a long-term follow-up study, the surviving cohort of SHARP-ER is a selected group of the original study participants, which may limit the generalizability of the findings. Conclusion: The SHARP-ER study will contribute important evidence on the long-term outcomes of cholesterol-lowering therapy in patients with advanced CKD with a total of 10 years of follow-up. Novel analyses of the socioeconomic impact of CKD over time will guide resource allocation. Trial Registration: The SHARP trial was registered at ClinicalTrials.gov NCT00125593 and ISRCTN 54137607.

19.
JCI Insight ; 4(23)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31622281

RESUMO

Mice homozygous for a hypomorphic allele of DNA replication factor minichromosome maintenance protein 2 (designated Mcm2cre/cre) develop precursor T cell lymphoblastic leukemia/lymphoma (pre-T LBL) with 4-32 small interstitial deletions per tumor. Mice that express a NUP98-HOXD13 (NHD13) transgene develop multiple types of leukemia, including myeloid and T and B lymphocyte. All Mcm2cre/cre NHD13+ mice develop pre-T LBL, and 26% develop an unrelated, concurrent B cell precursor acute lymphoblastic leukemia (BCP-ALL). Copy number alteration (CNA) analysis demonstrated that pre-T LBLs were characterized by homozygous deletions of Pten and Tcf3 and partial deletions of Notch1 leading to Notch1 activation. In contrast, BCP-ALLs were characterized by recurrent deletions involving Pax5 and Ptpn1 and copy number gain of Abl1 and Nup214 resulting in a Nup214-Abl1 fusion. We present a model in which Mcm2 deficiency leads to replicative stress, DNA double strand breaks (DSBs), and resultant CNAs due to errors in DNA DSB repair. CNAs that involve critical oncogenic pathways are then selected in vivo as malignant lymphoblasts because of a fitness advantage. Some CNAs, such as those involving Abl1 and Notch1, represent attractive targets for therapy.

20.
J Phys Chem B ; 123(42): 8931-8938, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31553603

RESUMO

A combination of surface tension, surface-specific vibrational spectroscopy, and differential scanning calorimetry experiments was performed to examine the ability of lipid films to enrich interfacial organic content by attracting soluble, neutral saccharides from bulk aqueous solution. This "cooperative adsorption" hypothesis has been proposed as a possible source of the high organic fractions found in sea spray aerosols and is believed to be responsible for cryoprotection in some organisms. Experiments described in this work show that the neutral disaccharide trehalose (Tre) is drawn to lipid films composed of dipalmitoylphosphatidylcholine (DPPC), a saturated lipid that is a major component of most eukaryotic cells. The effects of Tre on DPPC monolayer structure and organization were tested with tightly packed monolayers in the two-dimensional solid phase (40 Å2/molecule) and more expanded monolayers in the two-dimensional liquid condensed phase (55 Å2/molecule). Surface tension data show that DPPC monolayer behavior remains largely unchanged until Tre bulk concentrations are sufficiently high (≥50 mM). In contrast, surface-specific vibrational sum frequency spectra show that when Tre bulk concentrations are ≥10 mM, DPPC monolayers in their liquid condensed state (55 Å2/molecule) became more ordered, implying relatively strong noncovalent interactions between the two species. Tre also induces changes in DPPC bilayer behavior as evidenced by a gel-to-liquid crystalline phase transition temperature that increases with increasing Tre concentration. This result suggests that Tre associates with the DPPC headgroups in very specific ways leading to partial dehydration. Together, these results support the cooperative adsorption mechanism under some circumstances, namely, that there is a minimum aqueous phase Tre concentration required to induce observable structural changes in a lipid monolayer and that these effects are most pronounced with DPPC monolayers in their liquid condensed state compared to those of a tightly packed two-dimensional solid.

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