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1.
Dev Biol ; 457(2): 191-205, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325453

RESUMO

The identification of disease-causing mutations has in recent years progressed immensely due to whole genome sequencing approaches using patient material. The task accordingly is shifting from gene identification to functional analysis of putative disease-causing genes, preferably in an in vivo setting which also allows testing of drug candidates or biotherapeutics in whole animal disease models. In this review, we highlight the advances made in the field of bone diseases using small laboratory fish, focusing on zebrafish and medaka. We particularly highlight those human conditions where teleost models are available.


Assuntos
Doenças Ósseas/genética , Doenças Ósseas/fisiopatologia , Oryzias/genética , Peixe-Zebra/genética , Animais , Pesquisa Biomédica , Modelos Animais de Doenças , Genoma/genética , Sequenciamento Completo do Genoma
2.
Ethique Sante ; 18(2): 134-141, 2021 Jun.
Artigo em Francês | MEDLINE | ID: mdl-33897855

RESUMO

INTRODUCTION: The current new SARS-CoV-2 pandemic has had a profound impact on medical practice. The objective was to analyse the ethical questions raised by the French ENT community during the first wave of COVID-19 infections. METHODS: Four open-ended questions concerning ethical considerations in ENT were sent out in April 2020: (i) difficulties to care for COVID-19 positive patients; (ii) impact of the health crisis on COVID-19 negative patients; (iii) communication within the healthcare teams and with hospital staff; and (iv) management of information by the press, or national ENT societies. A thematic analysis was carried out and crossed with the epidemiological data of each respondent. RESULTS: Thirty-one responses from 13 different French Departments, including 21 from public institutions and 10 from private practice, median age of 45 and 17 men for 14 women, were analysed. The main ethical considerations concerned the management by ENTs of COVID-19 positive patients, the modification of practices in consultation and in the operating room, the fear of loss of chance for COVID-19 negative patients, the appropriate use of teleconsultations and teleworking and the consequences of fake-news for the population. CONCLUSION: In preparation of possible future pandemic outbreaks, key ethical aspects are to adapt patient management to local resources and infection prevalence, and circulate clear institutional guidelines.

3.
Diabet Med ; 36(3): 366-375, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30242901

RESUMO

AIMS: Children and adolescents with a family history of diabetes are at increased risk of overweight, but little is known about the potentially beneficial effects of physical activity on these children. The objective of this study was to investigate the association between moderate to vigorous physical activity (MVPA) and metabolic and inflammatory risks in children and adolescents with a family background of Type 1 diabetes or gestational diabetes. METHODS: Valid MVPA measurements, made with accelerometers, were available from 234 participants (median age, 10.2 years) who had a first-degree relative with either Type 1 or gestational diabetes. Anthropometric and metabolic measurements were made and cytokines measured, and were correlated with MVPA measurements, with stepwise adjustment for confounding factors, in a cross-sectional analysis. RESULTS: MVPA was negatively associated with insulin and C-peptide during challenge with an oral glucose tolerance test. MVPA was also significantly positively associated with the insulin sensitivity index, whereas no consistently significant associations were found between MVPA and BMI, blood pressure or cytokine levels. DISCUSSION: Our findings indicate that physical activity may have beneficial effects on insulin and C-peptide metabolism in children and adolescents with a family background of diabetes, but show no evidence of a protective association with other health-related outcomes.


Assuntos
Peptídeo C/sangue , Diabetes Mellitus Tipo 1 , Diabetes Gestacional , Exercício Físico/fisiologia , Glucose/farmacologia , Insulina/sangue , Anamnese , Adolescente , Criança , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Gestacional/epidemiologia , Feminino , Alemanha/epidemiologia , Teste de Tolerância a Glucose , Humanos , Masculino , Anamnese/estatística & dados numéricos , Gravidez , Fatores de Risco
4.
Nature ; 490(7420): 373-5, 2012 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-23075986

RESUMO

It is assumed that the radioactive decay of (44)Ti powers the infrared, optical and ultraviolet emission of supernova remnants after the complete decay of (56)Co and (57)Co (the isotopes that dominated the energy balance during the first three to four years after the explosion) until the beginning of active interaction of the ejecta with the surrounding matter. Simulations show that the initial mass of (44)Ti synthesized in core-collapse supernovae is (0.02-2.5) × 10(-4) solar masses (M circled dot). Hard X-rays and γ-rays from the decay of this (44)Ti have been unambiguously observed from Cassiopeia A only, leading to the suggestion that values of the initial mass of (44)Ti near the upper bound of the predictions occur only in exceptional cases. For the remnant of supernova 1987A, an upper limit to the initial mass of (44)Ti of <10(-3) M circled dot has been obtained from direct X-ray observations, and an estimate of (1-2) × 10(-4) M circled dot has been made from infrared light curves and ultraviolet spectra by complex and model-dependent computations. Here we report observations of hard X-rays from the remnant of supernova 1987A in the narrow band containing two direct-escape lines of (44)Ti at 67.9 and 78.4 keV. The measured line fluxes imply that this decay provided sufficient energy to power the remnant at late times. We estimate that the initial mass of (44)Ti was (3.1 ± 0.8) × 10(-4), which is near the upper bound of theoretical predictions.

5.
Scand J Immunol ; 85(4): 300-307, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28199728

RESUMO

We and others have previously identified microRNAs (miRNAs) with pathological roles in animal models of asthma, where miR-146a and miR-155 have been described to play important roles in inflammatory responses. To date, few studies have investigated miRNA expression in human asthmatics. In the current study, significantly lower levels of miR-155 were detected in cell-free sputum from allergic asthmatics compared to healthy controls. Induced sputum isolated from allergic asthmatics in and out of pollen season revealed that miR-155 expression, but not miR-146a, is reduced in lymphocytes in season compared to post-season. In contrast, miR-155 was found to increase, whereas miR-146a decreased in PBMCs and cell-free PBMC culture media upon T cell receptor stimulation via αCD3/CD28 in both allergic asthmatics and healthy controls. Our findings suggest that miR-155 is differentially expressed ex vivo in airways of allergic asthmatics compared to healthy controls, which may have implications in the local immune response in allergic asthma.


Assuntos
Asma/genética , Asma/imunologia , Citocinas/imunologia , MicroRNAs/genética , Sistema Respiratório/imunologia , Escarro/citologia , Adulto , Alérgenos/imunologia , Asma/patologia , Eosinófilos/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
BMC Cancer ; 17(1): 894, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29282036

RESUMO

BACKGROUND: A wide range of studies has investigated the diagnostic proficiency of extracellular microRNAs (miRNAs) in hepatocellular cancer (HCC). HCC is expected to increase in Sub-Saharan Africa (SSA), due to endemic levels of viral infection (HBV/HIV), ageing and changing lifestyles. This unique aetiological background provides an opportunity for investigating potentially novel circulating miRNAs as biomarkers for HCC in a prospective study in South Africa. METHODS: This study will recruit HCC patients from two South African cancer hospitals, situated in Durban and Pietermaritzburg in the province of KwaZulu-Natal. These cases will include both HBV mono-infected and HBV/HIV co-infected HCC cases. The control group will consist of two (2) age and sex-matched healthy population controls per HCC case randomly selected from a Durban based laboratory. The controls will exclude patients if they have any evidence of chronic liver disease. A standardised reporting approach will be adopted to detect, quantify and normalize the level of circulating miRNAs in the blood sera of HCC cases and their controls. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) will be employed to quantity extracellular miRNAs. Differences in concentration of relevant miRNA by case/control status will be assessed using the Wilcoxon rank-sum (Mann-Whitney U) test. Adjustment for multiple testing (Bonferroni correction), receiver operating curves (ROC) and optimal breakpoint analyses will be employed to identify potential thresholds for the differentiation of miRNA levels of HCC cases and their controls. DISCUSSION: Although there is a growing base of literature regarding the role of circulating miRNAs as biomarkers, this promising field remains a 'work in progress'. The aetiology of HBV infection in HCC is well understood, as well as it's role in miRNA deregulation, however, the mediating role of HIV infection is unknown. HCC incidence in SSA, including South Africa, is expected to increase significantly in the next decade. A combination of factors, therefore, offers a unique opportunity to identify candidate circulating miRNAs as potential biomarkers for HBV/HIV infected HCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , MicroRNA Circulante/genética , Infecções por HIV/complicações , HIV-1/isolamento & purificação , Neoplasias Hepáticas/diagnóstico , MicroRNAs/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Seguimentos , Perfilação da Expressão Gênica , Infecções por HIV/virologia , HIV-1/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Prognóstico , Estudos Prospectivos , Curva ROC
7.
Fortschr Neurol Psychiatr ; 84 Suppl 1: S41-7, 2016 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-27276072

RESUMO

Geriatric patients with Parkinson's disease (PD) represent a particular challenge in terms of diagnostics and treatment. This overview article addresses age-related characteristics of this patient group and discusses particularities in PD symptoms in this age group, frequent comorbidities and the resulting polypharmacy. Questions regarding the availability of specialist and therapist care as well as end-of-life aspects are discussed. While comprehensive care structures are not always available, this patient group requires a multidisciplinary treatment team supervised by neurologists with ample experience in PD treatment.


Assuntos
Geriatria , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Idoso , Idoso de 80 Anos ou mais , Humanos
8.
Fortschr Neurol Psychiatr ; 84(7): 404-10, 2016 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-27471998

RESUMO

Patients with advanced Parkinson's disease and motor complications undergoing optimized oral therapy can significantly benefit from continuous intrajejunal levodopa/carbidopa infusion applied by means of a medication pump. However, this requires a correctly positioned PEG-J tube and finely adjusted pump settings. Although this method is a routine procedure in specialist centers, no standard procedure has been defined up to now. For this reason, an expert recommendation regarding the practical application has been developed in order to standardize the procedure and facilitate patient access to this treatment option.


Assuntos
Antiparkinsonianos/administração & dosagem , Carbidopa/administração & dosagem , Bombas de Infusão Implantáveis , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/efeitos adversos , Carbidopa/efeitos adversos , Ensaios Clínicos como Assunto , Duodeno , Desenho de Equipamento , Gastrostomia , Humanos , Jejuno , Levodopa/efeitos adversos , Exame Neurológico/efeitos dos fármacos
9.
Clin Immunol ; 160(2): 282-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26111479

RESUMO

Children born by Caesarean Section have a higher risk for type 1 diabetes. We aimed to investigate whether Caesarean Section leads to alterations of the immune response in children with familial risk for type 1 diabetes. We examined measures of innate and adaptive immune responses in 94 prospectively followed children, including 40 born by Caesarean Section. Proinflammatory serum cytokine concentrations were determined at age 6 months. As a measure of vaccine response, IgG1, IgG2, and IgG4 tetanus antibody titers and CD4(+) T cell proliferation against tetanus toxoid were quantified. Compared to infants born by vaginal delivery, infants born by Caesarean Section had lower concentrations of the cytokines IFN-É£ (p=0.014) and IL-8 (p=0.005), and weaker CD4(+) T cell responses to tetanus measured in the first (p=0.007) and second year (p=0.047) of life. Overall, our findings provide evidence that the mode of delivery influences the immune status and responsiveness during childhood.


Assuntos
Imunidade Adaptativa/imunologia , Cesárea , Diabetes Mellitus Tipo 1/imunologia , Interferon gama/imunologia , Interleucina-8/imunologia , Toxoide Tetânico/imunologia , Anticorpos Antibacterianos/imunologia , Linfócitos T CD4-Positivos , Estudos de Casos e Controles , Parto Obstétrico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunoglobulina G , Lactente , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-1beta/imunologia , Interleucina-2/imunologia , Interleucina-6/imunologia , Masculino , Estudos Prospectivos , Toxina Tetânica/imunologia , Fator de Necrose Tumoral alfa/imunologia
10.
Allergy ; 70(10): 1288-99, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26011647

RESUMO

BACKGROUND: Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma. METHODS: Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells. RESULTS: Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (P = 1.7 × 10(-6) ) and ORMDL2 (P = 4.9 × 10(-5) ) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease-associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1. CONCLUSIONS: Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness.


Assuntos
Asma/genética , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Mutação , Fatores Etários , Alelos , Asma/imunologia , Asma/metabolismo , Estudos de Casos e Controles , Mapeamento Cromossômico , Epistasia Genética , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana/metabolismo , Família Multigênica , Razão de Chances , Polimorfismo de Nucleotídeo Único , Ligação Proteica
11.
Int J Obes (Lond) ; 38(12): 1491-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24694666

RESUMO

OBJECTIVES: Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. METHODS: Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. RESULTS: The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age 4 (odds ratio, 2.41; 95% confidence interval, 1.21-4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes. CONCLUSIONS: The HLA-DQ2/2 genotype may predispose to obesity among 2-4-year-old children with genetic risk for type 1 diabetes.


Assuntos
Autoanticorpos/genética , Autoimunidade/genética , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Obesidade Infantil/genética , Idade de Início , Peso ao Nascer , Estatura , Índice de Massa Corporal , Peso Corporal , Pré-Escolar , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Finlândia/epidemiologia , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Humanos , Ilhotas Pancreáticas , Masculino , Programas de Rastreamento , Mães , Obesidade Infantil/epidemiologia , Obesidade Infantil/imunologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Suécia/epidemiologia , Estados Unidos/epidemiologia
12.
Diabetologia ; 56(8): 1705-1711, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23657799

RESUMO

AIMS/HYPOTHESIS: Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes. METHODS: We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls. RESULTS: Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes. CONCLUSIONS/INTERPRETATION: These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Vírus/genética , Autoimunidade/genética , Autoimunidade/imunologia , Pré-Escolar , Diabetes Mellitus Tipo 1/virologia , Feminino , Humanos , Lactente , Recém-Nascido , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Masculino , Viroses/genética
13.
Haemophilia ; 19(1): 113-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22958194

RESUMO

Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.


Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII/genética , Haplótipos/genética , Hemofilia A/genética , Autoanticorpos/sangue , Estudos de Coortes , Análise Mutacional de DNA , Fator VIII/antagonistas & inibidores , Predisposição Genética para Doença , Hemofilia A/imunologia , Humanos , Mutação
14.
Genes Immun ; 13(7): 549-55, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22932816

RESUMO

Genome-wide association studies have identified gene regions associated with type 1 diabetes. The aim of this study was to determine how the combined allele frequency of multiple susceptibility genes can stratify islet autoimmunity and/or type 1 diabetes risk. Children of parents with type 1 diabetes and prospectively followed from birth for the development of islet autoantibodies and diabetes were genotyped for single-nucleotide polymorphisms at 12 type 1 diabetes susceptibility genes (ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10 and COBL). Non-human leukocyte antigen (HLA) risk score was defined by the total number of risk alleles at these genes. Receiver operator curve analysis showed that the non-HLA gene combinations were highly effective in discriminating diabetes and most effective in children with a high-risk HLA genotype. The greatest diabetes discrimination was obtained by the sum of risk alleles for eight genes (IFIH1, CTLA4, PTPN22, IL18RAP, SH2B3, KIAA0350, COBL and ERBB3) in the HLA-risk children. Non-HLA-risk allele scores stratified risk for developing islet autoantibodies and diabetes, and progression from islet autoimmunity to diabetes. Genotyping at multiple susceptibility loci in children from affected families can identify neonates with sufficient genetic risk of type 1 diabetes to be considered for early intervention.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Adolescente , Criança , Pré-Escolar , Frequência do Gene , Loci Gênicos , Antígenos HLA/genética , Humanos , Lactente , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem
16.
Strahlenther Onkol ; 188(3): 243-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22294198

RESUMO

PURPOSE: The goal of the present study was to assess the frequency and impact of replanning triggered solely by soft tissue changes observed on the daily setup mega-voltage CT (MVCT) in head and neck cancer (H&N) helical tomotherapy (HT). MATERIAL AND METHODS: A total of 11 patients underwent adaptive radiotherapy (ART) using MVCT. Preconditions were a soft tissue change > 0.5 cm and a tight mask. The dose­volume histograms (DVHs) derived from the initial planning kVCT (inPlan), the recalculated DVHs of the fraction (fx) when replanning was decided (actSit) and the DVHs of the new plan (adaptPlan) were compared. Assessed were the following: maximum dose (Dmax), minimum dose (Dmin), and mean dose (Dmean) to the planning target volume (PTV) normalized to the prescribed dose; the Dmean/fx to the parotid glands (PG), oral cavity (OC), and larynx (Lx); and the Dmax/fx to the spinal cord (SC) in Gy/fx. RESULTS: No patient had palpable soft tissue changes. The median weight loss at the moment of replanning was 2.3 kg. The median PTV Dmean was 100% for inPlan, 103% for actSit, and 100% for adaptPlan. The PTV was always covered by the prescribed dose. A statistically significant increase was noted for all organs at risk (OAR) in the actSit. The Dmean to the Lx, the Dmean to the OC and the Dmax to the SC were statistically better in the adaptPlan. No statistically significant improvement was achieved by ART for the PGs. No significant correlations between weight and volume loss or between the volume changes of the organs to each other were observed, except a strong positive correlation of the shrinkage of the PGs (ρ = + 0.77, p = 0.005). CONCLUSION: Soft tissue shrinkage without clinical palpable changes will not affect the coverage of the PTV, but translates into a higher delivered dose to the PTV itself and the normal tissue outside the PTV. The gain by ART in individual patients­especially in patients who receive doses close to the tolerance doses of the OAR­could be substantial.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Radioterapia de Intensidade Modulada , Tomografia Computadorizada Espiral , Humanos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Carga Tumoral , Redução de Peso
17.
Strahlenther Onkol ; 188(5): 410-6, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22367410

RESUMO

PURPOSE: The goal of this work was to assess the feasibility of moderately hypofractionated simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) with helical tomotherapy in patients with localized prostate cancer regarding acute side effects and dose-volume histogram data (DVH data). METHODS: Acute side effects and DVH data were evaluated of the first 40 intermediate risk prostate cancer patients treated with a definitive daily image-guided SIB-IMRT protocol via helical tomotherapy in our department. The planning target volume including the prostate and the base of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. The boost volume containing the prostate and 3 mm safety margins (5 mm craniocaudal) was treated as SIB to a total dose of 76 Gy (2.17 Gy per fraction). Planning constraints for the anterior rectal wall were set in order not to exceed the dose of 76 Gy prescribed to the boost volume. Acute toxicity was evaluated prospectively using a modified CTCAE (Common Terminology Criteria for Adverse Events) score. RESULTS: SIB-IMRT allowed good rectal sparing, although the full boost dose was permitted to the anterior rectal wall. Median rectum dose was 38 Gy in all patients and the median volumes receiving at least 65 Gy (V65), 70 Gy (V70), and 75 Gy (V75) were 13.5%, 9%, and 3%, respectively. No grade 4 toxicity was observed. Acute grade 3 toxicity was observed in 20% of patients involving nocturia only. Grade 2 acute intestinal and urological side effects occurred in 25% and 57.5%, respectively. No correlation was found between acute toxicity and the DVH data. CONCLUSION: This institutional SIB-IMRT protocol using daily image guidance as a precondition for smaller safety margins allows dose escalation to the prostate without increasing acute toxicity.


Assuntos
Neoplasias da Próstata/radioterapia , Radioterapia de Intensidade Modulada/efeitos adversos , Tomografia Computadorizada Espiral , Idoso , Idoso de 80 Anos ou mais , Trato Gastrointestinal/efeitos da radiação , Humanos , Masculino , Pessoa de Meia-Idade , Lesões por Radiação/etiologia , Reto/efeitos da radiação , Sistema Urogenital/efeitos da radiação
18.
Clin Exp Allergy ; 41(11): 1609-21, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21752117

RESUMO

BACKGROUND: The neuropeptide calcitonin gene-related peptide (CGRP) is released in the lung by sensory nerves during allergic airway responses. Pulmonary dendritic cells (DC) orchestrating the allergic inflammation could be affected by CGRP. OBJECTIVE: To determine the immunomodulatory effects of CGRP on DC function and its impact on the induction of allergic airway inflammation. METHODS: CGRP receptor expression on lung DC was determined by RT-PCR and immunofluorescence staining. The functional consequences of CGRP receptor triggering were evaluated in vitro using bone marrow-derived DC. DC maturation and the induction of ovalbumin (OVA)-specific T cell responses were analysed by flow cytometry. The in vivo relevance of the observed DC modulation was assessed in a DC-transfer model of experimental asthma. Mice were sensitized by an intrapharyngeal transfer of OVA-pulsed DC and challenged with OVA aerosol. The impact of CGRP pretreatment of DC on airway inflammation was characterized by analysing differential cell counts and cytokines in bronchoalveolar lavage fluid (BALF), lung histology and cytokine responses in mediastinal lymph nodes. RESULTS: RT-PCR, immunofluorescence and cAMP assay demonstrated the expression of functionally active CGRP receptors in lung DC. RT-PCR revealed a transcriptional CGRP receptor down-regulation during airway inflammation. CGRP specifically inhibited the maturation of in vitro generated DC. Maturation was restored by blocking with the specific antagonist CGRP(8-37) . Consequently, CGRP-pretreated DC reduced the activation and proliferation of antigen-specific T cells and induced increased the numbers of T regulatory cells. The transfer of CGRP-pretreated DC diminished allergic airway inflammation in vivo, shown by reduced eosinophil numbers and increased levels of IL-10 in BALF. CONCLUSIONS AND CLINICAL RELEVANCE: CGRP inhibits DC maturation and allergen-specific T cell responses, which affects the outcome of the allergic airway inflammation in vivo. This suggests an additional mechanism by which nerve-derived mediators interfere with local immune responses. Thus, CGRP as an anti-inflammatory mediator could represent a new therapeutic tool in asthma therapy.


Assuntos
Asma/imunologia , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Células Dendríticas/imunologia , Animais , Asma/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Linfócitos T/imunologia
19.
Nat Med ; 2(4): 405-11, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8597949

RESUMO

Major histocompatibility complex (MHC) genes (HLA in humans) regulate the immune response to foreign antigens. Molecular and serologic techniques were used to identify products of HLA class I, class II and transporter (TAP) genes (also part of the MHC) in homosexual seroconverters to human immunodeficiency virus type 1 (HIV-1). Comprehensive statistical analysis produced an HLA profile that predicted time from HIV-1 infection to the onset of AIDS. The profile was developed in a cohort of 139 men and evaluated in a second unrelated cohort of 102 men. In the evaluation cohort, the profile discriminated a sixfold difference between groups with the shortest and longest times to AIDS (P = 0.001). These findings support current theory about control of antigen processing by HLA genes and have implications for immunopathogenesis of HIV-1 and other infections.


Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Infecções por HIV/genética , HIV-1/isolamento & purificação , Complexo Principal de Histocompatibilidade/genética , Estudos de Coortes , Ligação Genética , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Antígenos de Histocompatibilidade Classe I/análise , Antígenos de Histocompatibilidade Classe II/análise , Humanos , Masculino , Análise de Sobrevida
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