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1.
BMC Public Health ; 22(1): 18, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991530

RESUMO

BACKGROUND: Occupational accidents continue to be a significant public health challenge worldwide. Construction workers in particular are at high risk of occupational accidents, and thus it is of major importance to identify possible predictors of occupational accidents among construction workers. We aimed to investigate the association between self-reported work pace and physical work demands and occupational accidents among ageing male construction workers in Denmark. METHODS: Data on perceived work pace, physical work demands, and occupational accidents was acquired from questionnaires sent to ageing construction workers in Denmark in 2016 as part of the ALFA project (ALdring og Fysisk Arbejde; Ageing and Physical Work). A sample of 1270 Danish male construction workers above 50 years of age was included in the present study. Multiple logistic regression models were applied, with adjustments for age, smoking, body mass index, musculoskeletal disorders, occupation, work experience, and support at work. RESULTS: Of 1270 construction workers, 166 (13.1%) reported an occupational accident within the last 12 months. There was no significant association between perceived work pace and occupational accidents, but physical work demands were associated with higher odds for occupational accidents, with an odds ratio of 2.27 (95% confidence interval 1.26-4.10) for medium physical work demands and 2.62 (95% confidence interval 1.50-4.57) for high physical work demands. CONCLUSIONS: Ageing male construction workers with high physical work demands had statistically significant higher odds of having an occupational accident. By contrast, perceived work pace was not associated with occupational accidents in this large cross-sectional study.

2.
Front Psychol ; 12: 719447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858259

RESUMO

Prediction is an important mechanism for efficient language processing. It has been shown that as a part of sentence processing, both children and adults predict nouns based on semantically constraining verbs. Language proficiency is said to modulate prediction: the higher proficiency, the better the predictive skill. Children growing up acquiring two languages are often more proficient in one of them, and as such, investigation of the predictive ability in young bilingual children can shed light on the role of language proficiency. Furthermore, according to production-based models, the language production system drives the predictive ability. The present study investigates whether bilingual toddlers predict upcoming nouns based on verb meanings in both their languages, and whether this ability is associated with expressive vocabulary. Seventeen Norwegian-English bilingual toddlers (aged 2;5-3;3), dominant in Norwegian, participated in the study. Verb-mediated predictive ability was measured via a visual world paradigm (VWP) experiment, including sentences with semantically constraining and neutral verbs. Expressive vocabulary was measured by MacArthur-Bates CDI II. The results suggested that the toddler group predicted upcoming noun arguments in both their dominant and non-dominant languages, but were faster in their dominant language. This finding highlights the importance of language dominance for predictive processing. There was no significant relationship between predictive ability and expressive vocabulary in either language.

3.
Front Cardiovasc Med ; 8: 764337, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805319

RESUMO

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms. Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE -/- Mfap4 -/-) and control apolipoprotein E-deficient (ApoE -/-) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE -/- Mfap4 -/- mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE -/- littermates. The ApoE -/- Mfap4 -/- AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-ß-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells. Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.

4.
Acta Physiol (Oxf) ; : e13731, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34519423

RESUMO

AIM: With diabetes comes a significant risk of macrovascular and microvascular complications. Circulating aldosterone levels increase in patients with diabetes. Aldosterone can directly affect vascular function via activation of the mineralocorticoid receptor (MR). We hypothesized that aldosterone via endothelial MR impairs endothelial function in a murine model of experimental diabetes. METHOD: Endothelial cell-specific mineralocorticoid receptor knockout MRflox/flox ;Tie2-Cre mice (ECMR-KO) and wild-type FVB littermates were subjected to an experimental type-1 diabetic model by low dose streptozotocin injections (55mg/kg/day) for five consecutive days. After 10 weeks of diabetes, second-order mesenteric resistance arteries were perfused ex vivo to evaluate vessel contractility and endothelial function. The effect of ex vivo incubation with aldosterone with and without the antagonist, spironolactone was determined. RESULTS: Diabetic ECMR-KO and wild-type mice had similar, elevated, plasma aldosterone concentration while only diabetic wild-type mice displayed elevated urine albumin excretion and cardiac and kidney hypertrophy at 10 weeks. There were no differences in contraction (Emax and EC50 ) to thromboxane receptor agonist (U46619) and elevated K+ between groups. Wild-type diabetic mice showed impaired acetylcholine (ACh)-dependent relaxation, while diabetic ECMR-KO mice had intact ACh-mediated relaxation. Aldosterone incubation ex vivo impaired ACh mediated relaxation and rendered responses similar to diabetic WT arteries. Direct, ex vivo aldosterone effects were absent in ECMR-KO animals. Ex vivo inhibitory effects of aldosterone on endothelial relaxation in arteries from WT were abolished by spironolactone. CONCLUSION: These findings show that endothelial cell mineralocorticoid receptor activation accounts for diabetes-induced systemic endothelial dysfunction in experimental diabetes and may explain the cardiovascular protection by MR antagonists in diabetes.

5.
Front Psychol ; 12: 688002, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349704

RESUMO

In this paper, we investigate a prosodic-phonetic feature in child-directed speech within a dynamic, complex, interactive theoretical framework. We focus on vocalic intrusions, commonly occurring in Norwegian word initial consonant clusters. We analysed child-directed speech from nine Norwegian-speaking mothers to their children, aged 2;6, 4, and 6 years, and compared the incidence and duration of vocalic intrusions in initial consonant clusters in these data with those in adult-directed speech and child speech. When viewed overall, vocalic intrusion was found to be similar in incidence in child- and adult-directed speech. However, closer examination revealed differential behaviour in child-directed speech for certain conditions. Firstly, a difference emerged for one particular phonetic context: While vocalic intrusions in /Cr/ clusters are frequent in adult-directed speech, their presence is near-categorical in child-directed speech. Secondly, we found that the duration of vocalic intrusions was longer in child- than in adult-directed speech, but only when directed to 2;6-year-olds. We argue that vocalic intrusions in child-directed speech may have both a bonding as well as a didactic function, and that these may vary according to the age of the child being addressed.

6.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445374

RESUMO

Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with a particular focus on NO- and 20-HETE-dependent pathways. As expected, dabigatran administration significantly delayed thrombin generation (CAT assay) in Ang II-treated hypertensive mice, and interestingly, it prevented endothelial dysfunction development, but it did not affect elevated blood pressure nor excessive aortic wall thickening. Dabigatran's effects on endothelial function in Ang II-treated mice were evidenced by improved NO-dependent relaxation in the aorta in response to acetylcholine in vivo (MRI measurements) and increased systemic NO bioavailability (NO2- quantification) with a concomitant increased ex vivo production of endothelium-derived NO (EPR analysis). Dabigatran treatment also contributed to the reduction in the endothelial expression of pro-inflammatory vWF and ICAM-1. Interestingly, the fall in systemic NO bioavailability in Ang II-treated mice was associated with increased 20-HETE concentration in plasma (UPLC-MS/MS analysis), which was normalised by dabigatran treatment. Taking together, the inhibition of thrombin activity in Ang II-induced hypertension in mice improves the NO-dependent function of vascular endothelium and normalises the 20-HETE-depedent pathway without affecting the blood pressure and vascular remodelling.


Assuntos
Angiotensina II/efeitos adversos , Antitrombinas/administração & dosagem , Dabigatrana/administração & dosagem , Ácidos Hidroxieicosatetraenoicos/sangue , Hipertensão/metabolismo , Remodelação Vascular/efeitos dos fármacos , Animais , Antitrombinas/farmacologia , Cromatografia Líquida , Dabigatrana/farmacologia , Modelos Animais de Doenças , Hipertensão/sangue , Hipertensão/induzido quimicamente , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Espectrometria de Massas em Tandem , Fator de von Willebrand/metabolismo
9.
J Neuromuscul Dis ; 8(4): 647-655, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33646172

RESUMO

BACKGROUND: Clinical characteristics of patients with congenital myopathies (CM) are well known but there is a lack of knowledge about the natural history and course of disease of the different genetic subtypes. In 2010 we assessed the national cohort of Danish patients with CM to decide genetic diagnosing and describe genotype- phenotype relationships.AIM of this follow-up study was to evaluate the course of disease since the initial study and to evaluate the applicability of standard assessment methods to reflect change over time and patients own opinion on the course of disease. METHODS: All available genetically diagnosed patients studied by us in 2010 (n = 41) were invited to the follow-up study; assessment of motor function (MFM-32), muscle strength (MRC %)and respiratory function (FVC %) and prime assessor were the same as in the initial study. Patients were asked whether the course of disease had progresses, was stable or had improved. RESULTS: 23 patients (15-61 y) accepted the invitation. Mean follow-up time was 7.7 years. Loss of muscle strength was more prominent in patients with mutations in DNM2, RYR1 and TPM2/3 genes and deterioration in FVC % was more evident in patients carrying NEB and ACTA1 gene mutations. MFM-sum score was less sensitive to change compared to MRC-sum score. In general, agreement between the patient's own opinion of the course of disease and results of assessments was good. CONCLUSION: The number of patients in the study is too small to be conclusive, but the results indicate that CM can be stable or slowly progressive depending on the genetic subtype.

10.
Acta Neurochir (Wien) ; 163(4): 959-967, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33389116

RESUMO

BACKGROUND: Primary malignant brain tumor is a severe disease with a poor prognosis causing reduced life expectancy and possible alteration in the perception of time. The aim of this study was to gain deeper insight into the perception of time from the perspective of patients with brain cancer as they pass through the Danish Integrated Brain Cancer Pathway at a university hospital in Denmark. METHODS: Data were generated by shadowing six patients and relatives during their visit to and hospitalisation in a neurosurgical department. RESULTS: Through one constructed case, three perspectives of time were identified. The patient's perception of time during his illness, the healthcare system's perception of time and, finally, an ethical time perspective. The analysis showed a discrepancy between patients' and healthcare professionals' perception of time. Furthermore, the results revealed an ethical time dimension. CONCLUSIONS: The findings contribute to a better understanding of the perception of time among seriously ill patients and may further healthcare professionals' awareness of how to support patients in achieving a more meaningful use of their remaining lifetime.


Assuntos
Neoplasias Encefálicas/psicologia , Percepção do Tempo , Adulto , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
11.
Life Sci ; 267: 118974, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33385407

RESUMO

AIM: We aimed to determine whether the sodium/glucose cotransporter family member SGLT3, a proposed glucose sensor, is expressed in the intestine and/or kidney, and if its expression is altered in mouse models of obesity and in humans before and after weight-loss surgery. MAIN METHODS: We used in-situ hybridization and quantitative PCR to determine whether the Sglt3 isoforms 3a and 3b were expressed in the intestine and kidney of C57, leptin-deficient ob/ob, and diabetic BTBR ob/ob mice. Western blotting and immunohistochemistry were also used to assess SGLT3 protein levels in jejunal biopsies from obese patients before and after weight-loss Roux-en-Y gastric bypass surgery (RYGB), and in lean healthy controls. KEY FINDINGS: Sglt3a/3b mRNA was detected in the small intestine (duodenum, jejunum and ileum), but not in the large intestine or kidneys of mice. Both isoforms were detected in epithelial cells (confirmed using intestinal organoids). Expression of Sglt3a/3b mRNA in duodenum and jejunum was significantly lower in ob/ob and BTBR ob/ob mice than in normal-weight littermates. Jejunal SGLT3 protein levels in aged obese patients before RYGB were lower than in lean individuals, but substantially upregulated 6 months post-RYGB. SIGNIFICANCE: Our study shows that Sglt3a/3b is expressed primarily in epithelial cells of the small intestine in mice. Furthermore, we observed an association between intestinal mRNA Sglt3a/3b expression and obesity in mice, and between jejunal SGLT3 protein levels and obesity in humans. Further studies are required to determine the possible role of SGLT3 in obesity.


Assuntos
Obesidade/metabolismo , Proteínas de Transporte de Sódio-Glucose/genética , Adulto , Animais , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Derivação Gástrica , Expressão Gênica , Humanos , Insulina/metabolismo , Resistência à Insulina , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Jejuno/metabolismo , Leptina/deficiência , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Obesidade/genética , Isoformas de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Transporte de Sódio-Glucose/biossíntese , Proteínas de Transporte de Sódio-Glucose/metabolismo , Transcriptoma , Perda de Peso
12.
Nephron ; 145(1): 27-34, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33105146

RESUMO

AIMS: The aim of this study was to evaluate the effect of liraglutide treatment on glucose variability and the risk of hypoglycemia by continuous glucose monitoring (CGM) in persons with type 2 diabetes (T2D) and dialysis-dependent end-stage renal disease (ESRD). MATERIALS AND METHODS: We assessed CGM data from a previous trial where 24 persons with T2D and dialysis-dependent ESRD were allocated (1:1) to 12 weeks of double-blinded treatment with liraglutide (titrated to maximum tolerable dose up to 1.8 mg) or placebo as an add-on to preexisting antidiabetic treatment. CGM (Ipro2®; Medtronic) was performed for up to 7 days at baseline and at weeks 2, 6, and 10. A linear mixed model was used to compare the 2 study arms. RESULTS: A CGM was worn at baseline by 12 persons in the liraglutide group and 10 in the placebo group (7 and 9 completed week 10, respectively). Glycated hemoglobin A1c (p = 0.81) and glucose variability was similar between the groups (standard deviation, p = 0.33; coefficient of variation, p = 0.16). Comparing baseline and week 10, the number of hypoglycemic events (glucose values between <3.9 and 3.0 mmol/L) increased in the liraglutide group compared with the placebo group (p = 0.02). The occurrence of hypoglycemic events below 3.0 mmol/L was similar between the groups (p = 0.36). CONCLUSIONS: In the present cohort of persons with T2D and dialysis-dependent ESRD, liraglutide treatment increased the risk of hypoglycemic events as compared to placebo (no difference was found for hypoglycemic events below 3.0 mmol/L). The majority of participants were co-treated with insulin.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Hipoglicemiantes/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Liraglutida/uso terapêutico , Diálise Renal , Idoso , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Placebos
13.
Acta Physiol (Oxf) ; 231(3): e13565, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33010104

RESUMO

AIM: Natriuretic peptides, BNP and ANP increase renal blood flow in experimental animals. The signalling pathway in human kidney vasculature is unknown. It was hypothesized that BNP and ANP cause endothelium-independent relaxation of human intrarenal arteries by vascular natriuretic peptide receptor-A, but not -B and -C, which is mimicked by agonists of soluble guanylyl cyclase sGC. METHODS: Human (n = 54, diameter: 665 ± 29 µm 95% CI) and control murine intrarenal arteries (n = 83, diameter 300 ± 6 µm 95% CI) were dissected and used for force recording by four-channel wire myography. Arterial segments were pre-contracted, then subjected to increasing concentrations of BNP, ANP, phosphodiesterase 5-inhibitor sildenafil, sGC-activator BAY 60-2770 and -stimulator BAY 41-2272. Endothelial nitric oxide synthase (eNOS) dependence was examined by use of L-NAME and eNOS knockout respectively. Molecular targets (NPR A-C, sGC, phosphodiesterase-5 and neprilysin) were mapped by PCR, immunohistochemistry and RNAscope. RESULTS: BNP, ANP, sildenafil, sGC-activation and -stimulation caused concentration-dependent relaxation of human and murine intrarenal arteries. BNP responses were independent of eNOS and were not potentiated by low concentration of phosphodiesterase-5-inhibitor, sGC-stimulator or NPR-C blocker. PCR showed NPR-A and C, phosphodiesterase-5, neprilysin and sGC mRNA in renal arteries. NPR-A mRNA and protein was observed in vascular smooth muscle and endothelial cells in arteries, podocytes, Bowmans capsule and vasa recta. NPR-C was observed in tubules, glomeruli and vasculature. CONCLUSION: Activation of transmembrane NPR-A and soluble guanylyl cyclase relax human preglomerular arteries similarly to phosphodiestase-5 inhibition. The human renal arterial bed relaxes in response to cGMP pathway.


Assuntos
Células Endoteliais , Guanilato Ciclase , Animais , Artérias , GMP Cíclico , Humanos , Camundongos , Peptídeos Natriuréticos/farmacologia , Guanilil Ciclase Solúvel
14.
J Clin Endocrinol Metab ; 106(3): e1262-e1270, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33247722

RESUMO

CONTEXT: Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and cardiovascular disease. Plasma aldosterone could contribute by reactive oxygen species-dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone. OBJECTIVE: We aimed to investigate the acute vascular effects of aldosterone in individuals with type 2 diabetes compared with healthy controls and if infusion of an antioxidant (n-acetylcysteine [NAC]) would alter the vascular response. METHODS: In a case-control design, 12 participants with type 2 diabetes and 14 healthy controls, recruited from the general community, were studied. Leg hemodynamics were measured before and during aldosterone infusion (0.2 and 5 ng min-1 [L leg volume]-1) for 10 minutes into the femoral artery with and without coinfusion of NAC (125 mg kg-1 hour-1 followed by 25 mg kg-1 hour-1). Leg blood flow and arterial blood pressure was measured, and femoral arterial and venous blood samples were collected. RESULTS: Compared with the control group, leg blood flow and vascular conductance decreased during infusion of aldosterone at the high dose in individuals with type 2 diabetes, whereas coinfusion of NAC attenuated this response. Plasma aldosterone increased in both groups during aldosterone infusion and there was no difference between groups at baseline or during the infusions. CONCLUSION: These results suggests that type 2 diabetes is associated with a vasoconstrictor response to physiological levels of infused aldosterone and that the antioxidant NAC diminishes this response.


Assuntos
Acetilcisteína/farmacologia , Aldosterona/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Vasoconstrição/efeitos dos fármacos , Acetilcisteína/administração & dosagem , Adulto , Aldosterona/administração & dosagem , Aldosterona/sangue , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Estudos de Casos e Controles , Dinamarca , Diabetes Mellitus Tipo 2/sangue , Feminino , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Perna (Membro)/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional/efeitos dos fármacos
15.
J Child Lang ; 48(1): 1-30, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32460919

RESUMO

Young children simplify word initial consonant clusters by omitting or substituting one (or both) of the elements. Vocalic insertion, coalescence and metathesis are said to be used more seldom (McLeod, van Doorn & Reed, 2001). Data from Norwegian children, however, have shown vocalic insertion to be more frequently used (Simonsen, 1990; Simonsen, Garmann & Kristoffersen, 2019). To investigate the extent to which children use this strategy to differing degrees depending on the ambient language, we analysed word initial cluster production acoustically in nine Norwegian and nine English speaking children aged 2;6-6 years, and eight adults, four from each language. The results showed that Norwegian-speaking children produce significantly more instances of vocalic insertions than English-speaking children do. The same pattern is found in Norwegian- versus English-speaking adults. We argue that this cross-linguistic difference is an example of the influence of prosodic-phonetic biases in language-specific developmental paths in the acquisition of speech.


Assuntos
Linguagem Infantil , Desenvolvimento da Linguagem , Fonética , Medida da Produção da Fala/estatística & dados numéricos , Adulto , Criança , Pré-Escolar , Inglaterra , Humanos , Masculino , Pessoa de Meia-Idade , Noruega
16.
J Am Heart Assoc ; 9(23): e016387, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33215566

RESUMO

Background Diabetic nephropathy is a common diabetes mellitus complication associated with hypertension, proteinuria, and excretion of urinary plasmin that activates the epithelial sodium channel, ENaC, in vitro. Here we hypothesized that the deletion of plasminogen and amiloride treatment protect against hypertension in diabetes mellitus. Methods and Results Male plasminogen knockout (plasminogen-deficient [Plg-/-]) and wild-type mice were rendered diabetic with streptozotocin. Arterial blood pressure was recorded continuously by indwelling catheters before and during 10 days of angiotensin II infusion (ANGII; 30-60 ng/kg per minute). The effect of amiloride infusion (2 mg/kg per day, 4 days) was tested in wild-type, diabetic ANGII-treated mice. Streptozotocin increased plasma and urine glucose concentrations and 24-hour urine albumin and plasminogen excretion. Diabetic Plg-/- mice displayed larger baseline albuminuria and absence of urine plasminogen. Baseline mean arterial blood pressure did not differ between groups. Although ANGII elevated blood pressure in wild-type, diabetic wild-type, and Plg-/- control mice, ANGII did not change blood pressure in diabetic Plg-/- mice. Compared with ANGII infusion alone, wild-type ANGII-infused diabetic mice showed blood pressure reduction upon amiloride treatment. There was no difference in plasma renin, ANGII, aldosterone, tissue prorenin receptor, renal inflammation, and fibrosis between groups. Urine from wild-type mice evoked larger amiloride-sensitive current than urine from Plg-/- mice with or without diabetes mellitus. Full-length γ-ENaC and α-ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa γ-ENaC cleavage product was increased in diabetic versus nondiabetic mice. Conclusions Plasmin promotes hypertension in diabetes mellitus with albuminuria likely through the epithelial sodium channel.


Assuntos
Amilorida/uso terapêutico , Angiotensina II/efeitos adversos , Diabetes Mellitus Tipo 1/complicações , Bloqueadores do Canal de Sódio Epitelial/uso terapêutico , Hipertensão/prevenção & controle , Plasminogênio/deficiência , Animais , Diabetes Mellitus Experimental , Canais Epiteliais de Sódio/efeitos dos fármacos , Hipertensão/diagnóstico , Hipertensão/etiologia , Masculino , Camundongos
17.
J Immunol ; 205(8): 2287-2300, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32938727

RESUMO

The complement system is an intricate cascade of the innate immune system and plays a key role in microbial defense, inflammation, organ development, and tissue regeneration. There is increasing interest in developing complement regulatory and inhibitory agents to treat complement dysfunction. In this study, we describe the nanobody hC3Nb3, which is specific for the C-terminal C345c domain of human and mouse complement component C3/C3b/C3c and potently inhibits C3 cleavage by the alternative pathway. A high-resolution structure of the hC3Nb3-C345c complex explains how the nanobody blocks proconvertase assembly. Surprisingly, although the nanobody does not affect classical pathway-mediated C3 cleavage, hC3Nb3 inhibits classical pathway-driven hemolysis, suggesting that the C-terminal domain of C3b has an important function in classical pathway C5 convertase activity. The hC3Nb3 nanobody binds C3 with low nanomolar affinity in an SDS-resistant complex, and the nanobody is demonstrated to be a powerful reagent for C3 detection in immunohistochemistry and flow cytometry. Overall, the hC3Nb3 nanobody represents a potent inhibitor of both the alternative pathway and the terminal pathway, with possible applications in complement research, diagnostics, and therapeutics.


Assuntos
Complemento C3b/imunologia , C5 Convertase da Via Alternativa do Complemento/imunologia , Via Alternativa do Complemento/imunologia , Anticorpos de Domínio Único/imunologia , Animais , Células HEK293 , Humanos , Camundongos , Domínios Proteicos
18.
Confl Health ; 14: 46, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32684948

RESUMO

Background: Despite the widely recognised importance of cultural adaptation to increase the effectiveness of psychological interventions, there is little guidance on its process. Developed based on existing theory, we applied a four-step process to culturally adapt a low-intensity psychological intervention for use in humanitarian settings. Methods: The four-step process was applied to adapt a WHO low-intensity psychological intervention (i.e. Problem Management Plus, or PM+) for use with displaced Venezuelans and Colombians in Colombia. First, a rapid desk review was used as an (1) information gathering tool to identify local population characteristics. Next, the results were taken forward for the (2) formulation of adaptation hypotheses, whereby PM+ protocols were screened to identify components for adaptation, drawing on the Ecological Validity Model. Third, the elements flagged for adaptation were taken forward for (3) local consultation to firstly, verify the components identified for adaptation, to identify other areas in need of adaptation, and thirdly, to adapt the intervention protocols. Finally, the adapted intervention protocols were reviewed through (4) external evaluations with local experts. Results: The information gathering phase yielded key information on the socioeconomic aspects of the groups targeted for intervention, the availability and need for mental health and psychosocial support, and existing barriers to accessing care. The adaptation hypotheses phase further identified the need for clearer explanations of key concepts, the need for sensitive topics to match local attitudes (e.g., domestic violence, thoughts of suicide), and the identification of culturally appropriate social supports. Building on these first two phases, local consultation subsequently resulted in revised PM+ protocols. The adapted protocols differed from the original format in their focus on the problems unique to these population groups, the way that psychological distress is expressed in this context, and the inclusion of locally available supports. The results of the external evaluation supported the adaptations made to the protocols. Conclusion: The proposed four-step process offers a useful guide for how to adapt low-intensity psychological intervention within humanitarian settings. Despite some limitations, we show that even when time and resources are scarce it is possible and necessary to culturally adapt psychological interventions. We invite further testing, replication, and improvements to this methodology.

19.
J Histochem Cytochem ; 68(6): 377-387, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32436776

RESUMO

Deleted in malignant brain tumors 1 (DMBT1) is part of the innate immune system and is expressed on mucosal surfaces in various tissues throughout the human body. However, to date, the localization of DMBT1 has not been investigated systematically and comprehensively in normal human tissues. In this study, we analyzed the mRNA expression of DMBT1 in human tissue by quantitative real-time PCR and examined its localization and distribution in the tissue by immunohistochemical staining using the monoclonal DMBT1 antibody HYB213-6. Anti-ovalbumin was used as an isotype control. The highest level of mRNA expression of DMBT1 was found in the small intestine, and the expression level was high throughout the luminal digestive tract. The expression of DMBT1 was especially high in the luminal digestive tract and salivary glands. The lowest expression level was found in the spleen. Immunohistochemical staining showed a high expression level of DMBT1 on mucosal surfaces throughout the body. There was a clear correlation between the mRNA expression and immunohistochemical expression of DMBT1 in the tissue. DMBT1 is strongly expressed on mucosal surfaces and in salivary glands.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Imuno-Histoquímica , Proteínas Supressoras de Tumor/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Humanos , Células MCF-7 , Especificidade de Órgãos , Transporte Proteico , Proteínas Supressoras de Tumor/genética
20.
Front Psychiatry ; 11: 212, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32265759

RESUMO

Armed conflict leads to increased risk of emotional distress among children and adolescents, and increased exposure to significant daily stressors such as poverty and community and family violence. Unfortunately, these increased risks usually occur in the context of largely unavailable mental health services. There is growing empirical support that evidence-based treatment techniques can be adapted and delivered by non-specialists with high fidelity and effectiveness. However, in order to improve feasibility, applicability, and outcomes, appropriate cultural and contextual adaptation is essential when delivering in different settings and cultures. This paper reports the adaptation process conducted on a new World Health Organization psychological intervention-Early Adolescent Skills for Emotions (EASE)-for use in the north of Lebanon. Lebanon is a middle-income country that hosts the largest number of refugees per capita globally. We conducted: i) a scoping review of literature on mental health in Lebanon, with a focus on Syrian refugees; ii) a rapid qualitative assessment with adolescents, caregivers, community members, and health professionals; iii) cognitive interviews regarding the applicability of EASE materials; iv) a psychologist review to reach optimal and consistent Arabic translation of key terms; v) "mock sessions" of the intervention with field staff and clinical psychology experts; vi) gathering feedback from the Training of Trainers workshop, and subsequent implementation of practice sessions; and vii) gathering feedback from the Training of Facilitators workshop, and subsequent implementation of practice sessions. Several changes were implemented to the materials-some were Lebanon-specific cultural adaptations, while others were incorporated into original materials as they were considered relevant for all contexts of adversity. Overall, our experience with adaptation of the EASE program in Lebanon is promising and indicates the acceptability and feasibility of a brief, non-specialist delivered intervention for adolescents and caregivers. The study informs the wider field of global mental health in terms of opportunities and challenges of adapting and implementing low-intensity psychological interventions in settings of low resources and high adversity.

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