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1.
Appetite ; 144: 104449, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520670

RESUMO

Alcohol use peaks in early adulthood and can contribute both directly and indirectly to unhealthy weight gain. This is the first qualitative study to explore the links between unhealthy eating behaviour and heavy alcohol use in the social, emotional and cultural lives of young adults. We conducted 45 in-depth interviews with 18-25-year-olds in North-East England to inform development of a dual-focused intervention to reduce health risk due to excess weight gain and alcohol use. Data were analysed thematically, following the principles of constant comparison, resulting in three intersecting themes: (1) how food and alcohol consumption currently link together for this population group; (2) influences upon linked eating and drinking behaviours and (3) young adults' feelings and concerns about linked eating and drinking behaviours. Socio-cultural, physical and emotional links between food and alcohol consumption were an unquestioned norm among young adults. Eating patterns linked to alcohol use were not tied only to hunger, but also to sociability, traditions and identity. Young adults conceptualised and calculated risks to weight, appearance and social status, rather than to long-term health. This study is the first to evidence the deeply interconnected nature of food and alcohol consumption for many young adults. Findings have important implications for intervention development, UK public health policy and practice, and point to a need for similar research in other countries.

2.
Trends Biochem Sci ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31679840

RESUMO

Ticks are hematophagous arachnids that parasitize mammals and other hosts, feeding on their blood. Ticks secrete numerous salivary factors that enhance host blood flow or suppress the host inflammatory response. The recruitment of leukocytes, a hallmark of inflammation, is regulated by chemokines, which activate chemokine receptors on the leukocytes. Ticks target this process by secreting glycoproteins called Evasins, which bind to chemokines and prevent leukocyte recruitment. This review describes the recent discovery of numerous Evasins produced by ticks, their classification into two structural and functional classes, and the efficacy of Evasins in animal models of inflammatory diseases. The review also proposes a standard nomenclature system for Evasins and discusses the potential of repurposing or engineering Evasins as therapeutic anti-inflammatory agents.

3.
BMC Cardiovasc Disord ; 19(1): 240, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664920

RESUMO

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

4.
Nat Commun ; 10(1): 3927, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

5.
Dev Psychol ; 55(10): 2203-2218, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368762

RESUMO

Epidemiological evidence links exposure to early life adversities-such as childhood maltreatment-with impaired health and well-being in adulthood. Since these effects are usually unrecognized or untreated in childhood, preventive and remediating interventions in adults are needed. Our focus on adulthood prompted three major questions. First, does our increased understanding of mechanisms accounting for the long-term effects of early life adversities help delineate underlying dimensions that underscore key similarities and differences among these adversities? Second, can adults accurately report on adversities they experienced in childhood? Third, can we identify malleable risk processes in adulthood that might be targets for preventive intervention? Supported by the National Institute on Aging, the U.K. Economic and Social and the Biotechnology and Biological Sciences Research Councils, a network of researchers in human and animal development addressed these questions through meetings and literature review. A small number of dimensions may adequately distinguish among a range of co-occurring childhood adversities. Widely used adult ascertainments of childhood adversity are poorly related to prospective ascertainment. Strategies for preventive interventions should be aimed both at adults who were actually exposed to adversity as well as those who recall adversity, but the targeted risk processes may be different. Now is an opportune time to support research on adult interventions based on unfolding research on critical periods of sensitivity to adversity in fetal and child development, on improved understanding of risk mechanisms that may persist across the life span, and on new insights on enhancing neuroplasticity in adults. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

6.
MedEdPORTAL ; 15: 10801, 2019 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31044155

RESUMO

Introduction: Knowledge and skill development related to communication must incorporate both affective and behavioral components, which are often difficult to deliver in a learning activity. Using theater techniques and principles can provide medical educators with tools to teach communication concepts. Methods: This 75-minute faculty development workshop presents a variety of techniques from theater and adapts them for use in medical education. Using examples related to diversity and inclusion, this session addresses general educational and theater principles, role-play, sociodrama, applied improvisation, and practical aspects of involving theater partners. The session materials include a PowerPoint presentation with facilitator notes, interactive activities to demonstrate each modality, and an evaluation. The sessions can be extended to longer formats as needed. Results: Forty-five participants at Learn Serve Lead 2016: The AAMC Annual Meeting attended the 75-minute session. We emailed 32 participants 5 months after the conference, and eight responded. Participants reported that their confidence level in using theater techniques as a tool for medical education increased from low-to-medium confidence presession to high confidence postsession. All survey respondents who were actively teaching said they had made changes to their teaching based on the workshop. All commented that they appreciated the active learning in the session. Many indicated they would appreciate video or other follow-up resources. Discussion: Principles and techniques from theater are effective tools to convey difficult-to-teach concepts related to communication. This workshop presents tools to implement activities in teaching these difficult concepts.

7.
BMJ Open ; 9(3): e024079, 2019 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-30904846

RESUMO

OBJECTIVES: Research on associations between childhood maltreatment and adult cardiometabolic disease risk is sparse. We aimed to investigate associations between different forms of child maltreatment and mid-adult cardiometabolic markers and whether potential intermediaries could account for the associations observed. SETTING: 1958 British birth cohort. PARTICIPANTS: Approximately 9000 cohort members with data on cardiometabolic markers. OUTCOMES: Adult (45y) cardiometabolic markers (blood pressure, lipids and glycated haemoglobin [HbA1c]). RESULTS: Seventeen per cent of participants were identified as neglected; 6.1%, 1.6% and 10.0% were identified as experiencing physical, sexual and psychological abuse, respectively. Childhood neglect and physical abuse were associated with high body mass index (BMI) and large waist circumference when adjusting for early-life covariates. For neglect, the adjusted odds ratio (AOR) was 1.16 (95% CI: 1.02 to 1.32) and 1.15 (1.02 to 1.30) for general and central obesity, respectively, and for physical abuse, the respective AOR was 1.36 (1.13 to 1.64) and 1.38 (1.16 to 1.65). Neglect was also associated with raised triglycerides by 3.9 (0.3 to 7.5)% and HbA1c by 1.2 (0.4 to 2.0)%, and among females, lower high-density lipoprotein cholesterol (HDL-c) by 0.05 (0.01 to 0.08)mmol/L after adjustment. For physical abuse, the AOR was 1.25 (1.00 to 1.56) for high low-density lipoprotein cholesterol, HbA1c was raised by 2.5 (0.7 to 4.3)% (in males) and HDL-c was lower by 0.06 (0.01 to 0.12)mmol/L (in females). Associations for sexual abuse were similar to those for physical abuse but 95% CIs were wide. For psychological abuse, the AOR for elevated triglycerides was 1.21 (1.02 to 1.44) and HDL-c was lower by 0.04 (0.01 to 0.07)mmol/L. Maltreatments were not associated with raised blood pressure. In analyses of potential intermediary factors, several associations attenuated after adjustment for adult lifestyles (mainly smoking and alcohol consumption rather than physical activity) and child-to-adult BMI. CONCLUSIONS: Childhood maltreatments, particularly neglect and physical abuse, were associated with greater adiposity and poorer lipid and HbA1c profiles decades later in adulthood. Associations were modest but independent of early-life factors linked to these outcomes. Findings implicate adult lifestyles as an important intermediary between child maltreatment and outcomes.

8.
Nutrients ; 10(10)2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30340361

RESUMO

Alcohol use peaks in early adulthood and can contribute both directly and indirectly to unhealthy weight gain. This review aimed to systematically evaluate the effectiveness of preventative targeted interventions focused on reducing unhealthy eating behavior and linked alcohol use in 18⁻25-year-olds. Twelve electronic databases were searched from inception to June 2018 for trials or experimental studies, of any duration or follow-up. Eight studies (seven with student populations) met the inclusion criteria. Pooled estimates demonstrated inconclusive evidence that receiving an intervention resulted in changes to self-reported fruit and vegetable consumption (mean change/daily servings: 0.33; 95% CI -0.22 to 0.87) and alcohol consumption (mean reduction of 0.6 units/week; CI -1.35 to 0.19). There was also little difference in the number of binge drinking episodes per week between intervention and control groups (-0.01 sessions; CI -0.07 to 0.04). This review identified only a small number of relevant studies. Importantly, included studies did not assess whether (and how) unhealthy eating behaviors and alcohol use link together. Further exploratory work is needed to inform the development of appropriate interventions, with outcome measures that have the capacity to link food and alcohol consumption, in order to establish behavior change in this population group.

9.
Nutrients ; 10(10)2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30309046

RESUMO

Evidence on the relationship between alcohol consumption and body mass index (BMI) is mixed, particularly for young adults. This study explored the relationship between energy obtained from alcoholic beverages and BMI using data for 18⁻25 year-olds (n = 7691) from pooled cross-sections of the 2008⁻2014 Health Survey for England and the Scottish Health Survey. Energy obtained from alcoholic beverages (excluding mixers) on the heaviest drinking day in the past week was expressed as percentage of total recommended dietary allowance (RDA) of energy (% RDA Energy). Linear regressions were estimated of BMI on alcohol intake categories controlling for intake frequency, physical activity, longstanding illness and other covariates, with separate analyses for men and women, and by beverage type. Significant associations with BMI were observed with the 'Very High' category of alcohol intake (>75% RDA Energy) for men (p < 0.001, 1.74, 95% confidence interval (CI) 0.98, 2.49) and with the "High" (>50% to 75% RDA Energy) (p < 0.001, 1.67, 95% CI 0.26, 2.58) and above category for women, when compared with the Low (>0⁻25% RDA Energy) category. Young adults drinking the highest levels of alcohol on a single occasion were more likely to be obese than those with the lowest intake. Interventions to address internationally rising youth obesity rates should also consider reducing alcohol consumption by increasing alcohol prices, and reducing availability and marketing exposure.

10.
Virulence ; 9(1): 1521-1538, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30289054

RESUMO

Streptococcus pneumoniae isolates express up to three neuraminidases (sialidases), NanA, NanB and NanC, all of which cleave the terminal sialic acid of glycan-structures that decorate host cell surfaces. Most research has focused on the role of NanA with limited investigations evaluating the roles of all three neuraminidases in host-pathogen interactions. We generated two highly potent monoclonal antibodies (mAbs), one that blocks the enzymatic activity of NanA and one cross-neutralizing NanB and NanC. Total neuraminidase activity of clinical S. pneumoniae isolates could be inhibited by this mAb combination in enzymatic assays. To detect desialylation of cell surfaces by pneumococcal neuraminidases, primary human tracheal/bronchial mucocilial epithelial tissues were infected with S. pneumoniae and stained with peanut lectin. Simultaneous targeting of the neuraminidases was required to prevent desialylation, suggesting that inhibition of NanA alone is not sufficient to preserve terminal lung glycans. Importantly, we also found that all three neuraminidases increased the interaction of S. pneumoniae with human airway epithelial cells. Lectin-staining of lung tissues of mice pre-treated with mAbs before intranasal challenge with S. pneumoniae confirmed that both anti-NanA and anti-NanBC mAbs were required to effectively block desialylation of the respiratory epithelium in vivo. Despite this, no effect on survival, reduction in pulmonary bacterial load, or significant changes in cytokine responses were observed. This suggests that neuraminidases have no pivotal role in this murine pneumonia model that is induced by high bacterial challenge inocula and does not progress from colonization as it happens in the human host.

11.
BMC Psychiatry ; 18(1): 297, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30236085

RESUMO

BACKGROUND: Obesity and depression are both highly prevalent public health disorders and evidence on their relationship is inconsistent. This study examined whether depressive symptoms are associated with current obesity, and further, whether obesity in turn is associated with an increased odds of depressive symptoms five years later after accounting for potential lifestyle confounders and depressive symptoms at baseline. METHODS: Data were obtained from the 1958 British birth cohort (N = 9217 for cross-sectional and 7340 for prospective analysis). Clinical Interview Schedule-Revised and Mental Health Inventory-5 were used for screening depressive symptoms at ages 45 and 50 years, respectively. General and central obesity were defined using measurements of body mass index (BMI) and waist circumference (WC) at 45 years, respectively. RESULTS: There was a cross-sectional association between depressive symptoms and obesity: participants with ≥2 depressive symptoms had 31% (95%CI 11% to 55%) higher odds of general and 26% higher odds of central obesity (95%CI 8% to 47%). In prospective analyses, both general and central obesity were associated with higher odds of depressive symptoms five years later among women but not in men (Pinteraction < 0.01). After adjustment for depressive symptoms at baseline, sociodemographic and lifestyle factors, women with general obesity had 38% (95% CI 7% to 77%) and women with central obesity 34% (95%CI 9% to 65%) higher odds of depression compared to others. CONCLUSIONS: Depressive symptoms are associated with concurrent obesity and related lifestyle factors among women and men in mid-life. Our study suggests that obesity in turn affects long-term risk of depressive symptoms in women but not in men, independently of concurrent associations, providing an important target group for the implementation of preventative strategies.

12.
J Contin Educ Health Prof ; 38(1): 73-78, 2018 Winter.
Artigo em Inglês | MEDLINE | ID: mdl-29369267

RESUMO

INTRODUCTION: In an era of competing priorities, funding is increasingly restricted for offices of faculty affairs and development. Opportunities for professional staff to grow and network through attendance at national meetings and to share best practices are limited. We sought to describe a community of practice established to enhance the professional development of faculty affairs professionals and to document its impact. METHODS: We outlined the process of formation of the New England Network for Faculty Affairs (NENFA), reviewed the pedagogical approaches to professional development, and surveyed members to evaluate the impact of NENFA on their activities, professional network and their institutions. RESULTS: After a successful 2011 initial meeting, NENFA created an organizing committee and conducted a needs assessment among potential members. NENFA's charter, mission, goals, and structure were based on survey results. NENFA's regional community of practice grew to 31 institutions and held 10 meetings over 5 years. Meetings have examined a faculty development topic in depth using multiple learning formats to engage participants from academic medical centers and allied professions. Results from a 2015 member survey confirmed the value of NENFA. Multiple members documented changes in practice as a result of participating. DISCUSSION: NENFA has been sustained by volunteer leadership, collaboration, and the value that the group has brought to its members. We propose that a "community of practice" offers an effective model for collaborative learning among individuals at different institutions within a competitive health care environment. We recommend that the approach be replicated in other regions.

13.
BMJ Open ; 7(10): e017900, 2017 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-29079607

RESUMO

OBJECTIVE: Child maltreatment (abuse and neglect) has established associations with mental health; however, little is known about its relationship with physical functioning. Physical functioning (ie, the ability to perform the physical tasks of daily living) in adulthood is an important outcome to consider, as it is strongly associated with an individual's ability to work, and future disability and dependency. We aimed to establish whether maltreatment was associated with physical functioning, independent of other early-life factors. SETTING: 1958 British birth cohort. PARTICIPANTS: 8150 males and females with data on abuse and who participated at age 50 years. OUTCOME MEASURES: The primary outcome was poor physical functioning at 50 years (<65 on the Short-Form 36 survey physical functioning subscale). Secondary outcomes included mental health and self-reported health at 50 years. RESULTS: 23% of participants reported at least one type of maltreatment; 12% were identified with poor physical functioning. Neglect (ORadj 1.55, 95% CI 1.24 to 1.93), psychological abuse (ORadj 1.49, 1.17-1.88) and sexual abuse (ORadj 2.56, 1.66-3.96) were associated with poor physical functioning independent of other maltreatments and covariates, including childhood social class, birth weight and childhood illness. Odds of poor physical functioning increased with multiple types of maltreatment (ptrend <0.001); ORadj ranged from 1.49 (1.23-1.82) for a single type to 2.09 (1.53-2.87) for those reporting > 3 types of maltreatment, compared with those with none. Associations of similar magnitude were observed for mental and self-reported health outcomes. CONCLUSIONS: Child neglect, psychological and sexual abuse were associated with poor physical functioning at 50 years, with accumulating risk for those with multiple types of maltreatment. Associations were independent of numerous early-life factors and were comparable in magnitude to those observed for mental health and self-rated health. Prevention or alleviation of the ill effects of maltreatment could be an effective policy intervention to promote healthy ageing.


Assuntos
Atividades Cotidianas , Envelhecimento , Maus-Tratos Infantis , Nível de Saúde , Aptidão Física , Criança , Abuso Sexual na Infância , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Estudos Prospectivos , Autorrelato , Classe Social , Inquéritos e Questionários
14.
Syst Rev ; 6(1): 42, 2017 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-28253914

RESUMO

BACKGROUND: Excess body weight and heavy alcohol consumption are two of the greatest contributors to global disease. Alcohol use peaks in early adulthood. Alcohol consumption can also exacerbate weight gain. A high body mass index and heavy drinking are independently associated with liver disease but, in combination, they produce an intensified risk of damage, with individuals from lower socio-economic status groups disproportionately affected. METHODS: We will conduct searches in MEDLINE, Embase, PubMed, PsycINFO, ERIC, ASSIA, Web of Knowledge (WoK), Scopus, CINAHL via EBSCO, LILACS, CENTRAL and ProQuest Dissertations and Theses for studies that assess targeted preventative interventions of any length of time or duration of follow-up that are focused on reducing unhealthy eating behaviour and linked risky alcohol use in 18-25-year-olds. Primary outcomes will be reported changes in: (1) dietary, nutritional or energy intake and (2) alcohol consumption. We will include all randomised controlled trials (RCTs) including cluster RCTs; randomised trials; non-randomised controlled trials; interrupted time series; quasi-experimental; cohort involving concurrent or historical controls and controlled before and after studies. Database searches will be supplemented with searches of Google Scholar, hand searches of key journals and backward and forward citation searches of reference lists of identified papers. Search records will be independently screened by two researchers, with full-text copies of potentially relevant papers retrieved for in-depth review against the inclusion criteria. Methodological quality of RCTs will be evaluated using the Cochrane risk of bias tool. Other study designs will be evaluated using the Cochrane Public Health Review Group's recommended Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Studies will be pooled by meta-analysis and/or narrative synthesis as appropriate for the nature of the data retrieved. DISCUSSION: It is anticipated that exploration of intervention effectiveness and characteristics (including theory base, behaviour change technique; modality, delivery agent(s) and training of intervention deliverers, including their professional status; and frequency/duration of exposure) will aid subsequent co-design and piloting of a future intervention to help reduce health risk and social inequalities due to excess weight gain and alcohol consumption. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016040128 .


Assuntos
Alcoolismo/prevenção & controle , Transtornos da Alimentação e da Ingestão de Alimentos/prevenção & controle , Revisão Sistemática como Assunto , Adolescente , Adulto , Humanos , Fatores de Risco , Comportamento de Redução do Risco , Adulto Jovem
16.
Virulence ; 8(7): 1203-1215, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28103139

RESUMO

Klebsiella pneumoniae ST258 is a globally distributed multi-drug resistant pathogen responsible for severe invasive infections. In this study, the different virulence potential of K. pneumoniae ST258 isolates in endotoxin susceptible versus resistant animal models was shown. Furthermore, ST258 clinical isolates were found highly sensitive to the bactericidal effect of naive animal and human serum. These observations imply that LPS, released from the rapidly lysed bacteria, may contribute to the high mortality associated with ST258 bacteremia cases. A humanized version (mAb A1102) of a previously described murine mAb specific for the conserved LPS O-antigen, was tested for endotoxin neutralization. A1102 was able to neutralize TLR-4 activation by ST258-derived LPS in vitro with an efficacy exceeding that of polymyxin B by 3 orders of magnitude. Passive immunization with A1102 afforded a significant level of protection in a galactosamine-sensitized mouse model of endotoxemia, induced by ST258-derived LPS, or upon challenge with live bacteria. Efficacy was retained using an aglycosylated IgG, as well as upon complement depletion, suggesting that Fc-independent endotoxin neutralization may be the main protective mechanism in this model, in spite of the complement-dependent bactericidal and opsonic activities additionally observed for A1102 in vitro. Furthermore, rabbits that are naturally highly susceptible to endotoxin, were also significantly protected by low doses of A1102 when challenged with an ST258 strain. Given this unique mode of action and the high protective efficacy of this mAb, passive immunization, as prophylactic or adjunct therapeutic approach for the treatment of infections caused by ST258 isolates should be considered.


Assuntos
Anticorpos Antibacterianos/imunologia , Anticorpos Monoclonais/imunologia , Endotoxinas/imunologia , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/imunologia , Antígenos O/imunologia , Animais , Anticorpos Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Feminino , Humanos , Imunização Passiva , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Neutralização , Coelhos , Ratos , Ratos Sprague-Dawley
17.
Lancet Diabetes Endocrinol ; 5(2): 97-105, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27908689

RESUMO

BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Análise da Randomização Mendeliana/métodos , Pró-Proteína Convertase 9/genética , Glicemia/metabolismo , Estudos de Casos e Controles , LDL-Colesterol/sangue , LDL-Colesterol/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
18.
Adv Exp Med Biol ; 1053: 119-153, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29549638

RESUMO

The failing efficacy of antibiotics and the high mortality rate among high-risk patients calls for new treatment modalities for bacterial infections. Due to the vastly divergent pathogenesis of human pathogens, each microbe requires a tailored approach. The main modes of action of anti-bacterial antibodies are virulence factor neutralization, complement-mediated bacterial lysis and enhancement of opsonophagocytic uptake and killing (OPK). Gram-positive bacteria cannot be lysed by complement and their pathogenesis often involves secreted toxins, therefore typically toxin-neutralization and OPK activity are required to prevent and ameliorate disease. In fact, the success stories in terms of approved products, in the anti-bacterial mAb field are based on toxin neutralization (Bacillus anthracis, Clostridium difficile). In contrast, Gram-negative bacteria are vulnerable to antibody-dependent complement-mediated lysis, while their pathogenesis rarely relies on secreted exotoxins, and involves the pro-inflammatory endotoxin (lipopolysaccharide). Given the complexity of bacterial pathogenesis, antibody therapeutics are expected to be most efficient upon targeting more than one virulence factor and/or combining different modes of action. The improved understanding of bacterial pathogenesis combined with the versatility and maturity of antibody discovery technologies available today are pivotal for the design of novel anti-bacterial therapeutics. The intensified research generating promising proof-of-concept data, and the increasing number of clinical programs with anti-bacterial mAbs, indicate that the field is ready to fulfill its promise in the coming years.


Assuntos
Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Imunoconjugados/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Animais , Antibacterianos/efeitos adversos , Antibacterianos/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Bactérias/imunologia , Bactérias/patogenicidade , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Citotoxicidade Imunológica , Interações Hospedeiro-Patógeno , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Fragmentos Fab das Imunoglobulinas/imunologia , Virulência
19.
Front Immunol ; 7: 208, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375615

RESUMO

Blood-sucking parasites, such as ticks, remain attached to their hosts for relatively long periods of time in order to obtain their blood meal without eliciting an immune response. One mechanism used to avoid rejection is the inhibition of the recruitment of immune cells, which can be achieved by a class of chemokine-binding proteins (CKBPs) known as Evasins. We have identified three distinct Evasins produced by the salivary glands of the common brown dog tick, Rhipicephalus sanguineus. They display different selectivities for chemokines, the first two identified show a narrow selectivity profile, while the third has a broader binding spectrum. The Evasins showed efficacy in animal models of inflammatory disease. Here, we will discuss the potential of their development for therapeutic use, addressing both the advantages and disadvantages that this entails.

20.
Psychoneuroendocrinology ; 73: 16-23, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27448524

RESUMO

Diurnal salivary cortisol profiles are valuable indicators of adrenocortical functioning in epidemiological research and clinical practice. However, normative reference values derived from a large number of participants and across a wide age range are still missing. To fill this gap, data were compiled from 15 independently conducted field studies with a total of 104,623 salivary cortisol samples obtained from 18,698 unselected individuals (mean age: 48.3 years, age range: 0.5-98.5 years, 39% females). Besides providing a descriptive analysis of the complete dataset, we also performed mixed-effects growth curve modeling of diurnal salivary cortisol (i.e., 1-16h after awakening). Cortisol decreased significantly across the day and was influenced by both, age and sex. Intriguingly, we also found a pronounced impact of sampling season with elevated diurnal cortisol in spring and decreased levels in autumn. However, the majority of variance was accounted for by between-participant and between-study variance components. Based on these analyses, reference ranges (LC/MS-MS calibrated) for cortisol concentrations in saliva were derived for different times across the day, with more specific reference ranges generated for males and females in different age categories. This integrative summary provides important reference values on salivary cortisol to aid basic scientists and clinicians in interpreting deviations from the normal diurnal cycle.


Assuntos
Ritmo Circadiano/fisiologia , Conjuntos de Dados como Assunto/estatística & dados numéricos , Hidrocortisona/metabolismo , Saliva/química , Estações do Ano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estados Unidos , Adulto Jovem
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