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1.
J Stroke Cerebrovasc Dis ; 29(2): 104530, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31813735

RESUMO

INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke disorder caused by mutations in the NOTCH3 gene. We report the first Chilean CADASIL family with complete radiological and histological studies. METHODS: The family tree was constructed from an autopsy-confirmed confirmed patient, and includes 3 generations. We performed clinical, pathologic, genetic, and radiologic examinations on members of a family with CADASIL. RESULTS: In the second generation, findings compatible with CADASIL were identified in 6 individuals, all of whom had a missense mutation in exon 3 (c.268C>T) resulting in an arginine to cysteine amino acid substitution at position 90 (R90C). In the third generation, a missense mutation was detected in one of the 4 asymptomatic individuals. CONCLUSIONS: There are similarities in clinical presentation between this family and previously described Asian and European series with R90C mutations. Detecting genotypes with a gain or loss of cysteine residues opens the door to future gene transfection-based therapies.

2.
J Vet Intern Med ; 34(1): 322-329, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31880352

RESUMO

BACKGROUND: Exercise-induced pulmonary hemorrhage (EIPH) is diagnosed and its severity assessed by post-exercise tracheobronchoscopy, and enumeration of bronchoalveolar lavage fluid red blood cells (BALFRBC). Minimal information is available regarding the relationship of tracheobronchoscopy score to BALFRBC number. OBJECTIVE: Evaluate the relationship between BALFRBC number and tracheobronchoscopy scores and determine their diagnostic sensitivities. ANIMALS: Nine sedentary horses, 21 fit Thoroughbreds, 129 Barrel Racers. METHODS: Normal BALFRBC number and the effect of bronchoalveolar lavage (BAL) on it were evaluated by performing 2 BALs 24 hours apart in sedentary horses. Tracheobronchoscopy followed by BAL was performed 247 times on 150 horses after treadmill, racetrack, or barrel racing exercise. Lastly, a BALFRBC diagnostic threshold number that optimized the geometric mean of the sensitivity and precision (F1-score) was determined using Bayesian analysis. RESULTS: No increase in BALFRBC occurred after the second BAL (mean ± SD, 304 ± 173/µL). Tracheobronchoscopy scores ranged from 0 (n = 112) to 4 (n = 4) and BALFRBC ranged from 102 to 4605268/µL. Spearman correlation between tracheobronchoscopy score and BALFRBC was weak (P < .001; rs = 0.42) with large ranges of BALFRBC associated with each tracheobronchoscopy score. The highest F1-score occurred for a BALFRBC threshold number = 992/µL. Seventy-five tracheobronchoscopy scores equaled 0 although BALFRBC number was ≥992/µL. Sensitivity of tracheobronchoscopy for diagnosing EIPH was poor (0.59; 95% confidence intervals [CI], 0.49-0.68), compared to BALFRBC number ≥992/µL (0.93; 95% CI, 0.88-0.96). CONCLUSIONS AND CLINICAL IMPORTANCE: False negatives are common with tracheobronchoscopy. Follow-up determination of BALFRBC may be indicated for tracheobronchoscopy scores = 0 before EIPH can be ruled out.

3.
Int J Clin Pract ; : e13453, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769902

RESUMO

BACKGROUND: Insulin resistance (IR) precedes the diagnosis of many metabolic and non-metabolic illnesses, including type 2 diabetes mellitus (T2DM). Acanthosis nigricans (AN) is a clinical sign associated with IR. However, AN prevalence and diagnostic accuracy in middle-age adults before or at the time of prediabetes/diabetes diagnosis remain uncertain. METHODS: With the aim to define AN prevalence and diagnostic accuracy, adults between 40 and 60 years of age were consecutively invited to participate in the study. Participants were categorised into one of two main groups: individuals with normoglycaemia (group 1) and hyperglycaemia (group 2 [ie, prediabetes/diabetes]). Demographic, clinical, anthropometric characteristics, homeostasis model assessment of IR, homeostatic model assessment of ß-cell function, as well as the presence of AN on the neck, axillae, elbows and knuckles were assessed. RESULTS: A total of 320 consecutive participants with a mean age of 49.3 years (59.4% women) were included. Overall, AN prevalence was 46.3%, while AN in group 1 and group 2 was 36.3% and 49.6%, respectively (P = .04). The most common affected sites in group 1 (n = 80) were the knuckles (21.2%) and the neck (17.5%), while in group 2 (n = 240), the neck (29.6%) followed by the knuckles (26.7%). The specificity and positive predictive value of AN for IR were 0.85 and 0.86 in group 1 and 0.90 and 0.96 in group 2, respectively. CONCLUSIONS: In middle-age adults, within the entire spectrum of carbohydrate tolerance, AN is highly prevalent and specific. This finding supports its assessment as a reliable and convenient clinical sign of IR. The understanding of AN behaviour through different carbohydrate tolerance strata, and its different locations, could lead to early detection of individuals at high metabolic risk or help direct a more pathophysiological treatment approach in patients with T2DM.

4.
Mult Scler J Exp Transl Clin ; 5(4): 2055217319884952, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695924

RESUMO

Background: Cuenca, a city in the Andean Region of southern Ecuador, has 591,996 inhabitants. A decade-old study showed the prevalence of multiple sclerosis in Cuenca was 0.75 cases per 100,000 inhabitants but no new epidemiological studies in this city have been performed since then. The aim of this study, conducted in 2016, was to update the prevalence records of multiple sclerosis in Cuenca. Methods: We performed a descriptive cross-sectional study in which we investigated prevalence rates in November of 2016. We estimated the prevalence of multiple sclerosis by cross-matching registries from the two neurological referral hospitals in Cuenca. Results: A total of 23 records were obtained from the two sources. The estimated prevalence was 3.88 per 100,000 inhabitants (95% confidence interval: 3.83-3.94). The disease was predominant among women (60%). The mean age of this cohort was 37 years (standard deviation ±12.4). Of the cases, 78% were relapsing-remitting multiple sclerosis. The mean Expanded Disability Status Scale score was 2.5. Conclusions: This study is an update to the first study conducted 10 years ago and shows the prevalence of multiple sclerosis in Cuenca has increased. However, the prevalence of multiple sclerosis is still low and very similar to that reported in neighbouring countries.

5.
Eur J Nutr ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31523780

RESUMO

BACKGROUND: The prevalence of overweight/obesity and related manifestations such as metabolic syndrome (MetS) is increasing worldwide. High energy density diets, usually with low nutrient density, are among the main causes. Some high-quality dietary patterns like the Mediterranean diet (MedDiet) have been linked to the prevention and better control of MetS. However, it is needed to show that nutritional interventions promoting the MedDiet are able to improve nutrient intake. OBJECTIVE: To assess the effect of improving MedDiet adherence on nutrient density after 1 year of follow-up at the PREDIMED-Plus trial. METHODS: We assessed 5777 men (55-75 years) and women (60-75 years) with overweight or obesity and MetS at baseline from the PREDIMED-Plus trial. Dietary changes and MedDiet adherence were evaluated at baseline and after 1 year. The primary outcome was the change in nutrient density (measured as nutrient intake per 1000 kcal). Multivariable-adjusted linear regression models were fitted to analyse longitudinal changes in adherence to the MedDiet and concurrent changes in nutrient density. RESULTS: During 1-year follow-up, participants showed improvements in nutrient density for all micronutrients assessed. The density of carbohydrates (- 9.0%), saturated fatty acids (- 10.4%) and total energy intake (- 6.3%) decreased. These changes were more pronounced in the subset of participants with higher improvements in MedDiet adherence. CONCLUSIONS: The PREDIMED-Plus dietary intervention, based on MedDiet recommendations for older adults, maybe a feasible strategy to improve nutrient density in Spanish population at high risk of cardiovascular disease with overweight or obesity.

6.
Arch Esp Urol ; 72(7): 662-669, 2019 Sep.
Artigo em Espanhol | MEDLINE | ID: mdl-31475677

RESUMO

OBJECTIVES: To describe the bladder management in spinal cord injury and to verify if the increase in the age of the patient who is suffering a spinal cord injury in recent years is conditioning a change in its treatment. METHODS: We performed a retrospective review of all acute traumatic spinal cord injured patients in Canary Islands between 2001-2015. Data were collected from the hospital records of a regional referral Spinal Cord Unit. RESULTS: The sample included 250 patients. Patients' mean age was observed to increase from 38 to 47 years during the study (p<0.05). Clean Intermittent Catheterization (CIC) was the most used bladder emptying method (42.4%), followed by normal voiding (NV) (26.4%) and permanent derivation (PD) (23.6%). There was a decrease in CIC use (48.1% to 40.3%) and an increase in PD use (13.5% to 32.5%) ( p<0.05 ). Cervical injuries were associated with NV (35.8%), while thoracic and lumbar injuries were associated with IC (67% and 41.7% respectively). Patients discharged to a health care residence were associated with IC (81.8%) (p<0.05). CONCLUSIONS: CIC is currently the most frequently used bladder emptying method in spinal cord injured patients in our population. The mean age of new spinal cord injury patients is progressively increasing and it promotes the use of indwelling catheter with an increased risk of urologic complications.


Assuntos
Traumatismos da Medula Espinal , Bexiga Urinaria Neurogênica/terapia , Adulto , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha , Cateterismo Urinário
7.
Eur J Intern Med ; 70: 24-32, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31451322

RESUMO

OBJECTIVE: To investigate the relationship between length of hospitalisation (LOH) and post-discharge outcomes in acute heart failure (AHF) patients and to ascertain whether there are different patterns according to department of initial hospitalisation. METHODS: Consecutive AHF patients hospitalised in 41 Spanish centres were grouped based on the LOH (<6/6-10/11-15/>15 days). Outcomes were defined as 90-day post-discharge all-cause mortality, AHF readmissions, and the combination of both. Hazard ratios (HRs), adjusted by chronic conditions and severity of decompensation, were calculated for groups with LOH >6 days vs. LOH <6 days (reference), and stratified by hospitalisation in cardiology, internal medicine, geriatrics, or short-stay units. RESULTS: We included 8563 patients (mean age: 80 (SD = 10) years, 55.5% women), with a median LOH of 7 days (IQR 4-11): 2934 (34.3%) had a LOH <6 days, 3184 (37.2%) 6-10 days, 1287 (15.0%) 11-15 days, and 1158 (13.5%) >15 days. The 90-day post-discharge mortality was 11.4%, readmission 32.2%, and combined endpoint 37.4%. Mortality was increased by 36.5% (95%CI = 13.0-64.9) when LOH was 11-15 days, and by 72.0% (95%CI = 42.6-107.5) when >15 days. Conversely, no differences were found in readmission risk, and the combined endpoint only increased 21.6% (95%CI = 8.4-36.4) for LOH >15 days. Stratified analysis by hospitalisation departments rendered similar post-discharge outcomes, with all exhibiting increased mortality for LOH >15 days and no significant increments in readmission risk. CONCLUSIONS: Short hospitalisations are not associated with worse outcomes. While post-discharge readmissions are not affected by LOH, mortality risk increases as the LOH lengthens. These findings were similar across hospitalisation departments.

8.
Nat Prod Res ; : 1-5, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31282206

RESUMO

The lupeol detection in callus of Vernonanthura patens (Kunth) H. Rob. leaves is discussed. Leaf segments previously treated with sodium hypochlorite, ethanol, and distilled water were placed in MS basal medium (Murashige and Skoog) for 7 days. Next, callus induction were done in two complemented MS medium for 6 weeks. Then, callus propagation were performed in MS medium supplemented with 1.0 mg/L of benzylaminopurine (BAP) and 0.5 mg/L of 2,4-dichlorophenoxyacetic acid (2,4-D) for 50 days. Fresh callus were extracted every 10 days in an ultrasonic bath using ethyl acetate (1.0 g/10 mL). The identification was carried out by Gas Chromatography-Mass Spectrometry (GC-MS) using selected ion monitoring (SIM) acquisition mode with characteristic ions of lupeol. The results obtained indicate the occurrence of lupeol in callus extract after twenty days of proliferation. These findings could be use in subsequent scale-up studies for biomass production containing this active compound in order to replace conventional methods.

9.
Nutrients ; 11(7)2019 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261967

RESUMO

Background: The effect of dietary fat intake on the metabolic syndrome (MetS) and in turn on cardiovascular disease (CVD) remains unclear in individuals at high CVD risk. Objective: To assess the association between fat intake and MetS components in an adult Mediterranean population at high CVD risk. Design: Baseline assessment of nutritional adequacy in participants (n = 6560, men and women, 55-75 years old, with overweight/obesity and MetS) in the PREvención con DIeta MEDiterránea (PREDIMED)-Plus randomized trial. Methods: Assessment of fat intake (total fat, monounsatured fatty acids: MUFA, polyunsaturated fatty acids: PUFA, saturated fatty acids: SFA, trans-fatty acids: trans-FA, linoleic acid, α-linolenic acid, and ω-3 FA) using a validated food frequency questionnaire, and diet quality using 17-item Mediterranean dietary questionnaire and fat quality index (FQI). Results: Participants in the highest quintile of total dietary fat intake showed lower intake of energy, carbohydrates, protein and fiber, but higher intake of PUFA, MUFA, SFA, TFA, LA, ALA and ω-3 FA. Differences in MetS components were found according to fat intake. Odds (5th vs. 1st quintile): hyperglycemia: 1.3-1.6 times higher for total fat, MUFA, SFA and ω-3 FA intake; low high-density lipoprotein cholesterol (HDL-c): 1.2 higher for LA; hypertriglyceridemia: 0.7 lower for SFA and ω-3 FA intake. Conclusions: Dietary fats played different role on MetS components of high CVD risk patients. Dietary fat intake was associated with higher risk of hyperglycemia.


Assuntos
Doenças Cardiovasculares/epidemiologia , Gorduras na Dieta/efeitos adversos , Dislipidemias/epidemiologia , Hiperglicemia/epidemiologia , Síndrome Metabólica/epidemiologia , Idoso , Biomarcadores/sangue , Glicemia/análise , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Estudos Transversais , Dieta Mediterrânea , Gorduras na Dieta/administração & dosagem , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/dietoterapia , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/dietoterapia , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/dietoterapia , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Espanha/epidemiologia , Resultado do Tratamento
10.
Arch Esp Urol ; 72(5): 483-499, 2019 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-31223126

RESUMO

OBJECTIVES: The purpose of this document is to establish practical recommendations on neurogenic bladder (NB) management based on scientific evidence and medical and nursing perspective in Spinal Cord Injury (SCI) Units as a first multidisciplinary consensual approach in Spain. METHODS: This paper reports results from the first modified Delphi consensus building exercise on this procedure. A committee of recognised opinion-leaders in rehabilitation and urology with special interest in NB was constituted. A working group formed by rehabilitation doctors, urologists and nursing staff of SCI and Neurorehabilitation Units of a number of Spanish hospitals and specialised centres associated with the panel of NB experts have prepared this document. RESULTS: This review provided an overview of the main aspects described by the different clinical guidelines already available and highlighted the need to focus on recommendations in special priority situations in which there was no consensus. In view of the considerable impact this condition has on quality of life, patients should be offered help to better understand the disorder and they should be taught how to use the treatment techniques to obtain satisfactory results and promote their autonomy. CONCLUSIONS: This article presents a version of guidelines for patients with NB. The guidelines define the clinical profile of patients to provide the best evidence- based care and also an overview of the current drug and surgical treatments of NB.


Assuntos
Bexiga Urinaria Neurogênica , Consenso , Humanos , Qualidade de Vida , Espanha , Bexiga Urinaria Neurogênica/diagnóstico , Bexiga Urinaria Neurogênica/terapia
11.
Eur J Heart Fail ; 21(11): 1353-1365, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31127677

RESUMO

OBJECTIVE: To compare the clinical characteristics and outcomes of patients with acute heart failure (AHF) according to clinical profiles based on congestion and perfusion determined in the emergency department (ED). METHODS AND RESULTS: Overall, 11 261 unselected AHF patients from 41 Spanish EDs were classified according to perfusion (normoperfusion = warm; hypoperfusion = cold) and congestion (not = dry; yes = wet). Baseline and decompensation characteristics were recorded as were the main wards to which patients were admitted. The primary outcome was 1-year all-cause mortality; secondary outcomes were need for hospitalisation during the index AHF event, in-hospital all-cause mortality, prolonged hospitalisation, 7-day post-discharge ED revisit for AHF and 30-day post-discharge rehospitalisation for AHF. A total of 8558 patients (76.0%) were warm + wet, 1929 (17.1%) cold + wet, 675 (6.0%) warm + dry, and 99 (0.9%) cold + dry; hypoperfused (cold) patients were more frequently admitted to intensive care units and geriatrics departments, and warm + wet patients were discharged home without admission. The four phenotypes differed in most of the baseline and decompensation characteristics. The 1-year mortality was 30.8%, and compared to warm + dry, the adjusted hazard ratios were significantly increased for cold + wet (1.660; 95% confidence interval 1.400-1.968) and cold + dry (1.672; 95% confidence interval 1.189-2.351). Hypoperfused (cold) phenotypes also showed higher rates of index episode hospitalisation and in-hospital mortality, while congestive (wet) phenotypes had a higher risk of prolonged hospitalisation but decreased risk of rehospitalisation. No differences were observed among phenotypes in ED revisit risk. CONCLUSIONS: Bedside clinical evaluation of congestion and perfusion of AHF patients upon ED arrival and classification according to phenotypic profiles proposed by the latest European Society of Cardiology guidelines provide useful complementary information and help to rapidly predict patient outcomes shortly after ED patient arrival.

12.
Eur J Intern Med ; 65: 69-77, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31076345

RESUMO

BACKGROUND: Little is known about the prevalence and impact of risk of malnutrition on short-term mortality among seniors presenting with acute heart failure (AHF) in emergency setting. The objective was to determine the impact of risk of malnutrition on 30-day mortality risk among older patients who attended in Emergency Departments (EDs) for AHF. MATERIAL AND METHODS: We performed a secondary analysis of the OAK-3 Registry including all consecutive patients ≥65 years attending in 16 Spanish EDs for AHF. Risk of malnutrition was defined by the Mini Nutritional Assessment Short Form (MNA-SF) < 12 points. Unadjusted and adjusted logistic regression models were used to assess the association between risk of malnutrition and 30-day mortality. RESULTS: We included 749 patients (mean age: 85 (SD 6); 55.8% females). Risk of malnutrition was observed in 594 (79.3%) patients. The rate of 30-day mortality was 8.8%. After adjusting for MEESSI-AHF risk score clinical categories (model 1) and after adding all variables showing a significantly different distribution among groups (model 2), the risk of malnutrition was an independent factor associated with 30-day mortality (adjusted OR by model 1 = 3.4; 95%CI 1.2-9.7; p = .020 and adjusted OR by model 2 = 3.1; 95%CI 1.1-9.0; p = .033) compared to normal nutritional status. CONCLUSIONS: The risk of malnutrition assessed by the MNA-SF is associated with 30-day mortality in older patients with AHF who were attended in EDs. Routine screening of risk of malnutrition may help emergency physicians in decision-making and establishing a care plan.

13.
PLoS Pathog ; 15(4): e1007658, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947296

RESUMO

Throughout evolution, cytomegaloviruses (CMVs) have been capturing genes from their hosts, employing the derived proteins to evade host immune defenses. We have recently reported the presence of a number of CD48 homologs (vCD48s) encoded by different pathogenic viruses, including several CMVs. However, their properties and biological relevance remain as yet unexplored. CD48, a cosignaling molecule expressed on the surface of most hematopoietic cells, modulates the function of natural killer (NK) and other cytotoxic cells by binding to its natural ligand 2B4 (CD244). Here, we have characterized A43, the vCD48 exhibiting the highest amino acid sequence identity with host CD48. A43, which is encoded by owl monkey CMV, is a soluble molecule released from the cell after being proteolytically processed through its membrane proximal region. A43 is expressed with immediate-early kinetics, yielding a protein that is rapidly detected in the supernatant of infected cells. Remarkably, surface plasmon resonance assays revealed that this viral protein binds to host 2B4 with high affinity and slow dissociation rates. We demonstrate that soluble A43 is capable to abrogate host CD48:2B4 interactions. Moreover, A43 strongly binds to human 2B4 and prevents 2B4-mediated NK-cell adhesion to target cells, therefore reducing the formation of conjugates and the establishment of immunological synapses between human NK cells and CD48-expressing target cells. Furthermore, in the presence of this viral protein, 2B4-mediated cytotoxicity and IFN-γ production by NK cells are severely impaired. In summary, we propose that A43 may serve as a functional soluble CD48 decoy receptor by binding and masking 2B4, thereby impeding effective NK cell immune control during viral infections. Thus, our findings provide a novel example of the immune evasion strategies developed by viruses.


Assuntos
Antígeno CD48/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Receptores Imunológicos/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Antígeno CD48/metabolismo , Células Cultivadas , Infecções por Citomegalovirus/virologia , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Ativação Linfocitária , Receptores Imunológicos/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo
14.
Chem Phys Lipids ; 219: 72-78, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30763541

RESUMO

In this work we used natural and modified cyclodextrins (ß-CD and HP-ß-CD) as encapsulating agents to improve citronellal properties. Using fluorimetric techniques, its aggregation behavior was studied for the first time. Its critical micellar concentration was seen to vary with the presence of cyclodextrins, which form 1:1 stoichiometry complexes with citronellal. The encapsulation constants and the scores obtained by Molecular Docking were correlated. Chromatographic (GC-MS) and sensory analysis confirmed that cyclodextrins improve the persistence of the aroma. Finally, the antimicrobial effect of citronellal against Escherichia coli and Bacillus subtilis in the presence and absence of cyclodextrins was studied. A combinatorial effect of citronellal, HP-ß-cyclodextrin and Glucobay® as an antimicrobial mixture was observed. The results of this study not only demonstrated the potential of CD mixtures, but also that the growth caused by CD digestion may sometimes be greater that the antimicrobial effect of the agents used in this study.


Assuntos
/química , Aldeídos/química , Anti-Infecciosos/química , Ciclodextrinas/química , Nanotecnologia , Óleos Voláteis/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Aldeídos/farmacologia , Anti-Infecciosos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Ligações de Hidrogênio , Micelas , Simulação de Acoplamento Molecular , beta-Ciclodextrinas/química
15.
PLoS One ; 14(2): e0212360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30779814

RESUMO

BACKGROUND: Trustworthy (i.e. low risk of bias) randomized clinical trials (RCTs) play an important role in evidence-based decision making. We aimed to systematically assess the risk of bias of trials published in high-impact endocrinology journals. METHODS: We searched the MEDLINE/PubMed database between 2014 and 2016 for phase 2-4 RCTs evaluating endocrine-related therapies. Reviewers working independently and in duplicate used the Cochrane Risk of Bias Tool (CCRBT) to determine the extent to which the methods reported protected the results of each RCT from bias. RESULTS: We assessed 292 eligible RCTs, of which 40% (116) were judged to be at low risk, 43% (126) at moderate, and 17% (50) at high risk of bias. Blinding of outcome assessment was the least common domain reported 43% (125), while selective reporting of outcomes was the most common 97% (282). In multivariable analysis, RCTs with a parallel design (OR 2.4; 95% CI; 1.2-4.6) and funded by for-profit sources (OR 2.2; 95% CI; 1.3-3.6) were more likely to be at low risk of bias. CONCLUSIONS: Trustworthy evidence should ultimately shape care to improve the likelihood of desirable patient outcomes. Six out-of 10 RCTs published in top endocrine journals are at moderate/high-risk of bias. Improving this should be a priority in endocrine research.


Assuntos
Doenças do Sistema Endócrino/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Doenças Ósseas/terapia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Bases de Dados Factuais , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Diabetes Mellitus/terapia , Doenças do Sistema Endócrino/metabolismo , Doenças do Sistema Endócrino/patologia , Humanos , Risco
16.
J Biol Chem ; 294(13): 5214-5227, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30723161

RESUMO

Etanercept is a soluble form of the tumor necrosis factor receptor 2 (TNFR2) that inhibits pathological tumor necrosis factor (TNF) responses in rheumatoid arthritis and other inflammatory diseases. However, besides TNF, etanercept also blocks lymphotoxin-α (LTα), which has no clear therapeutic value and might aggravate some of the adverse effects associated with etanercept. Poxviruses encode soluble TNFR2 homologs, termed viral TNF decoy receptors (vTNFRs), that display unique specificity properties. For instance, cytokine response modifier D (CrmD) inhibits mouse and human TNF and mouse LTα, but it is inactive against human LTα. Here, we analyzed the molecular basis of these immunomodulatory activities in the ectromelia virus-encoded CrmD. We found that the overall molecular mechanism to bind TNF and LTα from mouse and human origin is fairly conserved in CrmD and dominated by a groove under its 50s loop. However, other ligand-specific binding determinants optimize CrmD for the inhibition of mouse ligands, especially mouse TNF. Moreover, we show that the inability of CrmD to inhibit human LTα is caused by a Glu-Phe-Glu motif in its 90s loop. Importantly, transfer of this motif to etanercept diminished its anti-LTα activity in >60-fold while weakening its TNF-inhibitory capacity in 3-fold. This new etanercept variant could potentially be used in the clinic as a safer alternative to conventional etanercept. This work is the most detailed study of the vTNFR-ligand interactions to date and illustrates that a better knowledge of vTNFRs can provide valuable information to improve current anti-TNF therapies.


Assuntos
Vírus da Ectromelia/imunologia , Fatores Imunológicos/imunologia , Linfotoxina-alfa/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Receptores Chamariz do Fator de Necrose Tumoral/imunologia , Proteínas Virais/imunologia , Sequência de Aminoácidos , Animais , Vírus da Ectromelia/química , Ectromelia Infecciosa/virologia , Humanos , Fatores Imunológicos/química , Camundongos , Modelos Moleculares , Domínios Proteicos , Fator de Necrose Tumoral alfa/imunologia , Proteínas Virais/química
17.
Lung Cancer ; 128: 134-144, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30642446

RESUMO

OBJECTIVES: Tobacco smoking is strongly correlated with the onset and progression of non-small cell lung cancer (NSCLC). By activating α7 nicotinic acetylcholine receptors (α7-nAChRs) in these tumors nicotine and its tobacco-derived nitrosamine, NNK, contribute to these oncogenic processes. Here, we investigated whether the human-specific duplicated form of the α7-nAChR subunit (dupα7) behaves as an endogenous negative regulator of α7-nAChR-mediated tumorigenic activity induced by tobacco in NSCLC cells, similarly to its influence on other α7-nAChR-controlled functions in non-tumor cells. METHODS: Two human NSCLC cell lines, lung adenocarcinoma (A549) and squamous cell carcinoma of the lung (SK-MES-1), both wild-type or with stable overexpression of dupα7 (A549dupα7 or SK-MES-1dupα7), were used to investigate in vitro anti-tumor activity of dupα7 on nicotine- or NNK-induced tumor progression. For this purpose, migration, proliferation or epithelial-mesenchymal transition (EMT) were examined. The anti-tumor effect of dupα7 on nicotine-promoted tumor growth, proliferation or angiogenesis was also assessed in vivo in an athymic mouse model implanted with A549dupα7 or A549 xenografts. RESULTS: Overexpression of dupα7 in both cell lines almost completely suppresses the in vitro tumor-promoting effects induced by nicotine (1 µM) or NNK (100 nM) in wild-type cells. Furthermore, in mice receiving nicotine, A549dupα7 xenografts show: (i) a significant reduction of tumor growth, and (ii) decreased expression of cell markers for proliferation (Ki67) or angiogenesis (VEGF) compared to A549 xenografts. CONCLUSION: Our study demonstrates, for the first time, the in vitro and in vivo anti-tumor capacity of dupα7 to block the α7-nAChR-mediated tumorigenic effects of tobacco in NSCLC, suggesting that up-regulation of dupα7 expression in these tumors could offer a potential new therapeutic target in smoking-related cancers.


Assuntos
Duplicação Gênica , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Fumar/efeitos adversos , Receptor Nicotínico de Acetilcolina alfa7/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
19.
Med Sci (Basel) ; 6(3)2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087300

RESUMO

Chronic obstructive pulmonary disease (COPD) is the second leading cause of emergency department (ED) admissions to hospital, and nearly a third of patients with acute exacerbation (AE) of COPD are re-admitted to hospital within 28 days after discharge. It has been suggested that nearly a third of COPD admissions could be avoided through the implementation of evidence-based care interventions. A COPD discharge bundle is a set of evidence-based practices, aimed at improving patient outcomes after discharge from AE COPD; body of evidence supports the usefulness of discharge care bundles after AE of COPD, although there is a lack of consensus of what interventions should be implemented. On the other hand, the implementation of those interventions also involves different challenges. Important care gaps remain regarding discharge care bundles for patients with acute exacerbation of COPD discharged from EDs There is an urgent need for investigations to guide future implementation of care bundles for those patients discharged from EDs.

20.
J Biol Chem ; 293(36): 13874-13888, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30006348

RESUMO

The α7 nicotinic receptor subunit and its partially duplicated human-specific dupα7 isoform are coexpressed in neuronal and non-neuronal cells. In these cells, α7 subunits form homopentameric α7 nicotinic acetylcholine receptors (α7-nAChRs) implicated in numerous pathologies. In immune cells, α7-nAChRs are essential for vagal control of inflammatory response in sepsis. Recent studies show that the dupα7 subunit is a dominant-negative regulator of α7-nAChR activity in Xenopus oocytes. However, its biological significance in mammalian cells, particularly immune cells, remains unexplored, as the duplicated form is indistinguishable from the original subunit in standard tests. Here, using immunocytochemistry, confocal microscopy, coimmunoprecipitation, FRET, flow cytometry, and ELISA, we addressed this challenge in GH4C1 rat pituitary cells and RAW264.7 murine macrophages transfected with epitope- and fluorescent protein-tagged α7 or dupα7. We used quantitative RT-PCR of dupα7 gene expression levels in peripheral blood mononuclear cells (PBMCs) from patients with sepsis to analyze its relationship with PBMC α7 mRNA levels and with serum concentrations of inflammatory markers. We found that a physical interaction between dupα7 and α7 subunits in both cell lines generates heteromeric nAChRs that remain mainly trapped in the endoplasmic reticulum. The dupα7 sequestration of α7 subunits reduced membrane expression of functional α7-nAChRs, attenuating their anti-inflammatory capacity in lipopolysaccharide-stimulated macrophages. Moreover, the PBMC's dupα7 levels correlated inversely with their α7 levels and directly with the magnitude of the patients' inflammatory state. These results indicate that dupα7 probably reduces human vagal anti-inflammatory responses and suggest its involvement in other α7-nAChR-mediated pathophysiological processes.


Assuntos
Inflamação/fisiopatologia , Isoformas de Proteínas/metabolismo , Sepse/patologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Linhagem Celular , Retículo Endoplasmático/metabolismo , Humanos , Macrófagos , Camundongos , Hipófise/citologia , Isoformas de Proteínas/análise , Isoformas de Proteínas/genética , RNA Mensageiro/análise , Ratos , Sepse/metabolismo , Transfecção , Receptor Nicotínico de Acetilcolina alfa7/análise , Receptor Nicotínico de Acetilcolina alfa7/genética
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