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1.
Drugs Aging ; 41(4): 357-366, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38520626

RESUMO

BACKGROUND: Osteoarthritis (OA) is a major cause of chronic pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesics commonly used for musculoskeletal pain; however, NSAIDs can increase the risk of certain adverse events, such as gastrointestinal bleeding, edema, heart failure, and hypertension. OBJECTIVE: The objective of this study was to characterize existing comorbidities among patients with OA. For patients with OA with and without a coexisting medical condition of interest (CMCOI), we estimated the prevalence of prescribing and dispensing NSAIDs pre-OA and post-OA diagnosis. METHODS: Data from three large administrative claims databases were used to construct an OA retrospective cohort. Databases leveraged were IBM MarketScan Medicare Supplemental Database (MDCR), IBM MarketScan Commercial Database (CCAE), and Optum's de-identified Clinformatics® Data Mart Database (Optum CDM). The OA study population was defined to be those patients who had an OA diagnosis from an inpatient or outpatient visit with at least 365 days of prior observation time in the database during January 2000 through May 2021. Asthma, cardiovascular disorders, renal impairment, and gastrointestinal bleeding risks were the CMCOI of interest. Patients with OA were then classified as having or not having evidence of a CMCOI. For both groups, NSAID dispensing patterns pre-OA and post-OA diagnosis were identified. Descriptive analysis was performed within the Observational Health Data Sciences and Informatics framework. RESULTS: In each database, the proportion of the OA population with at least one CMCOI was nearly 50% or more (48.0% CCAE; 74.4% MDCR; 68.6% Optum CDM). Cardiovascular disease was the most commonly observed CMCOI in each database, and in two databases, nearly one in four patients with OA had two or more CMCOI (23.2% MDCR; 22.6% Optum CDM). Among the OA population with CMCOI, NSAID utilization post-OA diagnosis ranged from 33.0 to 46.2%. Following diagnosis of OA, an increase in the prescribing and dispensing of NSAIDs was observed in all databases, regardless of patient CMCOI presence. CONCLUSIONS: This study provides real-world evidence of the pattern of prescribing and dispensing of NSAIDs among patients with OA with and without CMCOI, which indicates that at least half of patients with OA in the USA have a coexisting condition. These conditions may increase the risk of side effects commonly associated with NSAIDs. Yet, at least 32% of these patients were prescribed and dispensed NSAIDs. These data support the importance of shared decision making between healthcare professionals and patients when considering NSAIDs for the treatment of OA in patients with NSAID-relevant coexisting medical conditions.


Assuntos
Doenças Cardiovasculares , Osteoartrite , Humanos , Idoso , Estados Unidos/epidemiologia , Estudos Retrospectivos , Medicare , Anti-Inflamatórios não Esteroides/efeitos adversos , Osteoartrite/complicações , Osteoartrite/tratamento farmacológico , Osteoartrite/epidemiologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/tratamento farmacológico
2.
BMJ Open ; 12(12): e066067, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36600332

RESUMO

INTRODUCTION: Familial hypercholesterolaemia (FH) is a frequent (1:300) autosomal dominantly inherited condition which causes premature (women <60 years, men <55 years) cardio-cerebrovascular disease (CVD). Early detection and initiation of treatment can prevent the development of CVD and premature death. Our pilot study aims to investigate the prevalence of FH, the feasibility and efficacy of a screening based on a capillary blood test performed during a school medicine visit in primary school children. METHODS AND ANALYSIS: In this cross-sectional study, all children (n=3200) between 7 and 12 years, attending primary school in the city of Luxembourg and invited for their mandatory medical school examinations between 2021 and 2023 are invited to participate. A study nurse performs a capillary blood test to analyse the lipid profile. Families receive the result including an interpretation and invitation to seek medical advice if indicated. If FH is confirmed, a reverse cascade screening in that family will be proposed. The child will receive standard care. Primary outcome is the occurrence of confirmed FH in the study population. Secondary outcomes include the percentage of children screened, percentage of children with abnormal lipid values, percentage of families screened and percentage of families with additionally identified members suffering from hypercholesterolaemia. A health economic analysis will be performed. ETHICS AND DISSEMINATION: Ethics approval (reference number 202108/01) has been obtained from the National Research Ethics Committee (CNER (Luxembourg)) and was authorised by the ministry of health in Luxembourg. Families receive written information with an informed consent form. Participation requires an informed consent form signed by the parents. The results will be disseminated in peer-reviewed publications, conference presentations and by public media to the general public. TRIAL REGISTRATION NUMBER: NCT05271305.


Assuntos
Doenças Cardiovasculares , Hiperlipoproteinemia Tipo II , Criança , Feminino , Humanos , Masculino , Estudos Transversais , Estudos de Viabilidade , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Lipídeos , Luxemburgo/epidemiologia , Projetos Piloto , Instituições Acadêmicas
3.
Allergy Asthma Clin Immunol ; 18(1): 56, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35725523

RESUMO

BACKGROUND: Air pollution may induce or reinforce nasal inflammation regardless of allergy status. There is limited direct clinical evidence informing the treatment of airborne pollution-related rhinitis. OBJECTIVE: To assess the effectiveness of intranasal budesonide in adults with self-reported rhinitis symptoms triggered/worsened by airborne pollution. METHODS: Adults in northern China with self-reported rhinitis symptoms triggered or worsened by airborne pollution were randomized to budesonide 256 µg/day or placebo for 10 days in pollution season (October 2019 to February 2020). The primary endpoint was the mean change from baseline in 24-h reflective total nasal symptom score (rTNSS) averaged over 10 days. The secondary endpoints were subject-assessed Global Impression of Change (SGIC), mean change from baseline in individual nasal symptom severity, and mean change from baseline in individual non-nasal symptoms of cough and postnasal drip severity. One-sided P < 0.0125 was considered statistically significant. RESULTS: After an interruption by COVID-19, an interim analysis showed that the study could be ended for efficacy with n = 206 participants (103/group) since the primary efficacy endpoint demonstrated significant results. The final efficacy results showed that the 10-day-averaged rTNSS change in the budesonide group was greater than with placebo (- 2.20 vs - 1.72, P = 0.0107). Budesonide also significantly improved 10-day-averaged itching/sneezing change (- 0.75 vs - 0.51, P = 0.0009). Results for SGIC and all other individual symptoms did not show significant differences between the two groups. CONCLUSIONS: Intranasal budesonide 256 µg once daily improved the total nasal symptoms and itching/sneezing over 10 days in adults with rhinitis triggered/worsened by airborne pollution.

4.
Biochim Biophys Acta ; 1798(7): 1301-8, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20226161

RESUMO

The feasibility of applying multiphoton excitation fluorescence microscopy-related techniques in planar membrane systems, such as lipid monolayers at the air-water interface (named Langmuir films), is presented and discussed in this paper. The non-linear fluorescence microscopy approach, allows obtaining spatially and temporally resolved information by exploiting the fluorescent properties of particular fluorescence probes. For instance, the use of environmental sensitive probes, such as LAURDAN, allows performing measurements using the LAURDAN generalized polarization function that in turn is sensitive to the local lipid packing in the membrane. The fact that LAURDAN exhibit homogeneous distribution in monolayers, particularly in systems displaying domain coexistence, overcomes a general problem observed when "classical" fluorescence probes are used to label Langmuir films, i.e. the inability to obtain simultaneous information from the two coexisting membrane regions. Also, the well described photoselection effect caused by excitation light on LAURDAN allows: (i) to qualitative infer tilting information of the monolayer when liquid condensed phases are present and (ii) to provide high contrast to visualize 3D membranous structures at the film's collapse pressure. In the last case, computation of the LAURDAN GP function provides information about lipid packing in these 3D structures. Additionally, LAURDAN GP values upon compression in monolayers were compared with those obtained in compositionally similar planar bilayer systems. At similar GP values we found, for both DOPC and DPPC, a correspondence between the molecular areas reported in monolayers and bilayers. This correspondence occurs when the lateral pressure of the monolayer is 26+/-2 mN/m and 28+/-3 mN/m for DOPC and DPPC, respectively.


Assuntos
2-Naftilamina/análogos & derivados , Lauratos/química , Membranas Artificiais , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Transição de Fase , 1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , 1,2-Dipalmitoilfosfatidilcolina/química , 2-Naftilamina/química , Fosfatidilcolinas/química
5.
Biomacromolecules ; 12(3): 681-91, 2011 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-21254766

RESUMO

It is demonstrated that water-soluble, glucosylated poly(pentafluorostyrene) derivatives revealed favorable coating material properties for magnetic iron oxide nanoparticles. To prepare the coating material in high reproducibility and purity as well as in sufficient amounts, a new route of synthesis is established. The preparation and characterization of the glucosylated, tetrafluorostyryl monomer, by thiol-para-fluorine "click" reaction, and its polymerization, via nitroxide-mediated radical process, is presented in detail. In addition, the coating material and the resulting particle properties are investigated by means of XPS, DLS, TGA, TEM, and cryo-TEM as well as flow cytometry. The glycopolymer acts as an appropriate stabilizing agent for the superparamagnetic nanoparticles by the formation of an approximately 10 nm thick shell, as shown by the XPS analysis. Furthermore, the application of FITC-labeled glycopolymer yielded fluorescent, superparamagnetic nanoparticles, which can be used for monitoring cell-carbohydrate interactions, because these particles show no cytotoxicity toward 3T3 fibroblasts.


Assuntos
Materiais Revestidos Biocompatíveis/síntese química , Magnetismo , Polimerização , Tioglicosídeos/química , Células 3T3 , Animais , Carboidratos , Citometria de Fluxo , Fluorescência , Camundongos
6.
Biotechnol Lett ; 33(5): 929-36, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21207110

RESUMO

Classical purification of the glycoprotein equine chorionic gonadotropin (eCG) from serum includes pH fractionation with metaphosphoric acid, two ethanol precipitation steps as well as dialysis followed by fixed-bed chromatography. A simplified process requiring only 1/3 of the solvent and improving the yield from 53 to 65% has been developed. The process comprises an ultra-/diafiltration step after the first ethanol precipitation, directly followed by an adsorption/desorption procedure based on magnetic microadsorbents with N,N-diethyl-ammonium functionalization. The process reaches an overall purification factor of eCG of more than 1800 and an average product activity of 1300 IU(ELISA)/mg. After adapting the parameters of the fractionation and the type of magnetic microadsorbents, the new concept is likely to be transferable to other serum proteins.


Assuntos
Gonadotropina Coriônica/isolamento & purificação , Glicoproteínas/isolamento & purificação , Magnetismo , Microesferas , Soro/química , Adsorção , Animais , Fracionamento Químico , Cavalos , Ultrafiltração/métodos
7.
Genes Chromosomes Cancer ; 49(3): 270-81, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19998449

RESUMO

Transforming growth factor beta1 (TGFB1) acts as a growth inhibitor of normal colonic epithelial cells, however, as a tumor promoter of colorectal cancer (CRC) cells. To explore the association between genetic polymorphisms in the TGFB1 pathway and CRC susceptibility and clinical outcome, we carried out a case-control study on a Swedish population of 308 CRC cases and 585 age- and gender-matched controls. The cases were sampled prospectively and had up to 16 years follow-up, making the study material particularly suitable for survival analysis. On the basis of their reported or predicted functional effect, nine single-nucleotide polymorphisms (TGFB1: Leu10Pro; TGFBR1: 9A/6A and IVS7G+24A; FURIN: C-229T; THBS1: T+42C; LTBP1L: C-256G; LTBP4: T-893G and Thr750Ala; BAMBI: T-779A) were selected for genotyping. We evaluated the associations between genotypes and CRC and Dukes' stage. Survival probabilities were compared between different subgroups. The observed statistically significant associations included a decreased CRC risk for TGFBR1 IVS7G+24A minor allele carriers (odds ratio (OR): 0.72, 95% confidence interval (CI): 0.53-0.97), less aggressive tumors with Dukes' stage A+B for carriers of LTBP4 Thr750Ala and BAMBI T-779A minor alleles (OR: 0.58, 95%CI: 0.36-0.93 and OR: 0.51, 95%CI: 0.29-0.89, respectively) and worse survival for FURIN C-229T heterozygotes (hazard ratio: 1.63, 95%CI: 1.08-2.46). As this is the first study about the influence of the polymorphisms in the TGFB1 pathway on CRC progression, further studies in large independent cohorts are warranted.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo Genético , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Progressão da Doença , Éxons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Neoplasias Retais/genética , Neoplasias Retais/patologia
8.
J Electrocardiol ; 43(2): 146-54, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19879594

RESUMO

BACKGROUND: Ventricular preexcitation may be associated with dilated cardiomyopathy, even in the absence of recurrent and incessant tachycardia. METHODS: This report describes the clinical and electrophysiologic characteristics of 10 consecutive children (6 males), with median age of 8 years (range, 1-17 years), who presented with dilated cardiomyopathy and overt ventricular preexcitation on the 12-lead electrocardiogram. Incessant tachycardia as the cause of dilated cardiomyopathy could be excluded. Coronary angiography, right ventricular endomyocardial biopsy (4/10 patients), and metabolic and microbiologic screening were nondiagnostic. RESULTS: The electrocardiograms suggested right-sided pathways in all patients. A right-sided accessory pathway was demonstrated in 8 patients during invasive electrophysiologic study (superoparaseptal, n = 5; septal, n = 2; fasciculoventricular, n = 1). All pathways were successfully ablated (radiofrequency ablation in 7, cryoablation in 1). Two patients had spontaneous loss of ventricular preexcitation during follow-up. Left ventricular (LV) function completely recovered after a loss of preexcitation in all patients. CONCLUSIONS: Right-sided accessory pathways with overt ventricular preexcitation and LV dyssynchrony may cause dilated cardiomyopathy. An association between such pathways and dilated cardiomyopathy is suggested by the rapid normalization of ventricular function and reverse LV remodeling after a loss of ventricular preexcitation.


Assuntos
Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico , Eletrocardiografia/métodos , Sistema de Condução Cardíaco/anormalidades , Complexos Ventriculares Prematuros/complicações , Complexos Ventriculares Prematuros/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
9.
Polymers (Basel) ; 12(2)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041295

RESUMO

Many of current bio-based materials are not fully or partly used for material utilization, as the composition of their raw materials and/or possible applications are unknown. This study deals with the analysis of the wood extractives from three different tissue of larch wood: Sapwood mainly from outer part of the log, and sound knotwood as well as dead knotwood. The extractions were performed with an accelerated solvent extractor (ASE) using hexane and acetone/water. The obtained extracts were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Three various vibrational spectroscopy (FT-RAMAN, FT-IR and FT-NIR) methods reflect the information from the extracts to the chemical composition of the types of wood before the extraction processes. Multivariate data analysis of the spectra was used to obtain a better insight into possible classification methods. Taxifolin and kaempferol were found in larger amount in sound knotwood samples compared to larch wood with high percentage of sapwood and dead knotwood samples. While the extractions of dead knotwood samples yielded more larixol and resin acids than the other larch wood samples used. Based on the chemical composition, three lead compounds were defined for the classification of the different wood raw materials. The vibrational spectroscopy methods were applied to show their potential for a possible distinction of the three types of larch wood tissue. This new insight into the different larch wood extracts will help in the current efforts to use more environmentally friendly raw materials for innovative applications. The connection between the raw materials and extraction yields of the target values is important to transform the results from the laboratory to industry and consumer applications.

11.
Biochim Biophys Acta ; 1778(1): 166-74, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17964533

RESUMO

Secretory phospholipase A2 (sPLA2) hydrolyzes phosphatidylcholines (PC) within lipid bilayers to produce lyso-PC and a fatty acid, which can act as signaling molecule in biological membranes. The activity of sPLA2 depends on the membrane structure. Bilayer defects, curvature, and gel-fluid micro-heterogeneity are known to activate sPLA2. Here, we investigate if liquid-liquid immiscibility within model membranes is sufficient for sPLA2 activation. The onset of the hydrolytic activity of cobra-venom sPLA2 towards mixed monolayers of dimyristoyl-PC (DMPC)/cholesterol 2:1 (mol/mol) has been determined using infrared reflection-absorption spectroscopy (IRRAS) and polarization-modulated (PM-) IRRAS. The lag phase of sPLA2 activity increases exponentially with rising surface pressures starting at 12 mN/m. This indicates that enzyme activation is hampered at higher surface pressures. Below 12 mN/m, no lag phase is observed, and sPLA2 is efficiently activated. The surface pressure that is critical for sPLA2 activation correlates with the critical miscibility pressure according to the phase diagram of DMPC and cholesterol. Thus, coexisting, liquid-phase domains provide sufficient boundaries to activate sPLA2. Moreover, liquid-liquid immiscibility is an activating mechanism for sPLA2 that also applies to biological membranes under physiological conditions because the corresponding bilayer structure is associated with that of membrane rafts.


Assuntos
Membranas Artificiais , Fosfolipases A2 Secretórias/metabolismo , Animais , Dimiristoilfosfatidilcolina/metabolismo , Venenos Elapídicos/enzimologia , Ativação Enzimática , Lisofosfatidilcolinas/metabolismo , Espectrofotometria Infravermelho , Fatores de Tempo
12.
Endocr Relat Cancer ; 14(3): 733-40, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17914103

RESUMO

Western lifestyle leading to obesity and type 2 diabetes has been associated with increased risk of colorectal cancer (CRC). Diet and related factors may affect the risk by modifying plasma insulin levels. Thus, the inter-individual variation in insulin signaling may play a plausible role in the development of CRC. We hypothesized that functional polymorphisms in the insulin pathway genes INS, INSR, IGFBPI, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with CRC. We studied the association of five single nucleotide polymorphisms (SNPs) with the risk of CRC using a hospital-based case-control design with 712 cases and 748 controls from the Czech Republic. The INSR A-603G promoter SNP, which is located within a known Sp1-binding site, was associated with the risk of CRC, with carriers of the G allele having a decreased risk (odds ratios (OR) 0.71, 95% confidence interval (CI) 0.54-0.93). Carrying the variant allele of the IRS1 Gly972Arg SNP further decreased the risk among the INSR-603G allele carriers (OR 0.28, 95% CI 0.11-0.70). SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. In conclusion, genetic variation in the insulin signaling pathway genes may affect the risk of CRC.


Assuntos
Antígenos CD/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Regiões Promotoras Genéticas , Receptor de Insulina/genética , Transdução de Sinais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Insulina/genética , Proteínas Substratos do Receptor de Insulina , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/genética , Receptor de Insulina/metabolismo , Fatores de Risco
13.
BMC Genet ; 8: 41, 2007 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-17598925

RESUMO

BACKGROUND: Copy number polymorphisms caused by genomic rearrangements like deletions, make a significant contribution to the genomic differences between two individuals and may add to disease predisposition. Therefore, genotyping of such deletion polymorphisms in case-control studies could give important insights into risk associations. RESULTS: We mapped the breakpoints and developed a fluorescent fragment analysis for a deletion disrupting the TRY6 gene to exemplify a quick and cheap genotyping approach for such structural variants. We showed that the deletion is larger than predicted and encompasses also the pseudogene TRY5. We performed a case-control study to test an association of the TRY6 deletion polymorphism with breast cancer using a single nucleotide polymorphism which is in 100% linkage disequilibrium with the deletion. We did not observe an effect of the deletion on breast cancer risk (OR 1.05, 95% CI 0.71-1.56). CONCLUSION: Although we did not observe an association between the TRY6 deletion polymorphism and breast cancer risk, the identification and investigation of further deletions using the present approach may help to elucidate their effect on disease susceptibility.


Assuntos
Neoplasias da Mama/genética , Deleção de Genes , Tripsinogênio/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Primers do DNA , Feminino , Genótipo , Homozigoto , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Alinhamento de Sequência , Tripsina
14.
Chem Phys Lipids ; 145(2): 119-27, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17187768

RESUMO

The monolayer structure of pure dipalmitoylphosphatidylcholine (DPPC) and equimolar mixtures of DPPC/n-hexadecanol (C(16)OH) and DPPC/dipalmitoylglycerol (DPG) are studied by the film balance technique and grazing incidence X-ray diffraction measurements. At 20 degrees C, the binary systems exhibit complete miscibility. In contrast to pure DPPC monolayers, a condensing effect is observed in the presence of both non-phospholipid additives; but the phase transition behavior differs. The tilt angle of the hydrocarbon chains in the DPPC/C(16)OH mixture is significantly smaller than in pure DPPC monolayers. The tilt of the chains is even further reduced in the mixed monolayer of DPPC/DPG. A comparison of the three systems reveals distinct structural features such as phase state, chain tilt, and molecular area over a wide range of surface pressures. Therefore, these monolayers provide a highly suitable model to investigate the influence of structural parameters on biological processes occurring at the membrane surface, e.g. enzymatic reactions and adsorption events.


Assuntos
1,2-Dipalmitoilfosfatidilcolina/química , Diglicerídeos/química , Álcoois Graxos/química , Membranas Artificiais , Varredura Diferencial de Calorimetria , Conformação Molecular , Tensão Superficial , Difração de Raios X
15.
J Clin Endocrinol Metab ; 91(4): 1513-9, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16434456

RESUMO

CONTEXT: The contribution of prolactin (PRL) through its receptor (PRLR) to the pathogenesis and progression of human mammary tumors has received recent attention. OBJECTIVE: We investigated whether genetic variation in the PRL and PRLR genes is associated with the risk of breast cancer (BC). DESIGN: We conducted a case-control study with a total of seven single nucleotide polymorphisms (SNPs). SETTING: The study was conducted at an academic research laboratory and university clinics. PATIENTS AND OTHER PARTICIPANTS: A total of 441 German familial, unrelated BC cases and 552 controls matched by age, ethnicity, and geographical region participated in the study. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES(S): SNP genotype and haplotype distributions and haplotype interactions were correlated with the risk of BC. RESULTS: Two SNPs (rs1341239 and rs12210179) within the PRL promoter regions were significantly associated with increased risk in homozygotes for the variant alleles [odds ratio (OR), 1.67 and 95% confidence interval (CI), 1.11-2.50; and OR, 2.09 and 95% CI, 1.23-3.52, respectively]. The PRL haplotype containing the variant alleles of the promoter SNPs increased significantly the risk of BC (OR 1.42, 95%CI 1.07-1.90). A PRLR haplotype was associated with a significant decrease in BC risk (OR 0.69, 95% CI 0.54-0.89). An increasing number of PRL and PRLR risk haplotypes led to a significant trend of increasing risk for BC (chi(2) = 12.15; P = 0.007). CONCLUSIONS: Genetic variation in the PRL and PRLR genes was shown to influence BC risk. Additional studies are needed to further clarify the role of the PRL and PRLR genes in the risk of BC.


Assuntos
Neoplasias da Mama/genética , Prolactina/genética , Receptores da Prolactina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , DNA/genética , Feminino , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prolactina/metabolismo , Receptores da Prolactina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Nat Genet ; 48(6): 648-56, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27158779

RESUMO

Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.


Assuntos
Ciliopatias/metabolismo , Flagelos/fisiologia , Proteínas/fisiologia , Animais , Humanos , Camundongos , Mutação , Fenótipo , Ligação Proteica , Transporte Proteico , Proteínas/genética
17.
Clin Case Rep ; 1(2): 86-90, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25356219

RESUMO

KEY CLINICAL MESSAGE: Diabetes in neonates is a monogenetic disease and genetic analysis is warranted to allow best treatment, prognosis, and genetic counseling. Transcription factor mutations may have a variable expression and different organs may be involved.

18.
PLoS One ; 7(4): e36003, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22558302

RESUMO

The toxicity of Loxosceles spider venom has been attributed to a rare enzyme, sphingomyelinase D, which transforms sphingomyelin to ceramide-1-phosphate. The bases of its inflammatory and dermonecrotic activity, however, remain unclear. In this work the effects of ceramide-1-phosphate on model membranes were studied both by in situ generation of this lipid using a recombinant sphingomyelinase D from the spider Loxosceles laeta and by pre-mixing it with sphingomyelin and cholesterol. The systems of choice were large unilamellar vesicles for bulk studies (enzyme kinetics, fluorescence spectroscopy and dynamic light scattering) and giant unilamellar vesicles for fluorescence microscopy examination using a variety of fluorescent probes. The influence of membrane lateral structure on the kinetics of enzyme activity and the consequences of enzyme activity on the structure of target membranes containing sphingomyelin were examined. The findings indicate that: 1) ceramide-1-phosphate (particularly lauroyl ceramide-1-phosphate) can be incorporated into sphingomyelin bilayers in a concentration-dependent manner and generates coexistence of liquid disordered/solid ordered domains, 2) the activity of sphingomyelinase D is clearly influenced by the supramolecular organization of its substrate in membranes and, 3) in situ ceramide-1-phosphate generation by enzymatic activity profoundly alters the lateral structure and morphology of the target membranes.


Assuntos
Ceramidas/química , Ceramidas/metabolismo , Membranas Artificiais , Diester Fosfórico Hidrolases/metabolismo , 2-Naftilamina/análogos & derivados , 2-Naftilamina/metabolismo , Animais , Varredura Diferencial de Calorimetria , Colesterol/metabolismo , Transferência Ressonante de Energia de Fluorescência , Cinética , Lauratos/metabolismo , Luz , Microscopia de Fluorescência , Fosfatidilcolinas , Espalhamento de Radiação , Esfingomielinas/metabolismo , Aranhas/enzimologia , Temperatura , Lipossomas Unilamelares/metabolismo
19.
Dent Mater ; 28(10): e239-49, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22727357

RESUMO

OBJECTIVES: Inflammatory periodontal diseases are accompanied by destruction of periodontal tissue and alveolar bone. Infrabony lesions can be regenerated with adequate bone substitutes, which require high biocompatibility of the material. METHODS: To rate the biocompatibility of nine polymeric periodontal bone substitutes (Bio 1-Bio 9), cell viability and cytotoxicity assays were performed. For viability, human gingival fibroblasts (HGFs) and MC3T3 osteoblasts were cultured on the bone substitutes. For cytotoxicity, biomaterial extracts were prepared by incubation with culture medium for maximally 28days, and cells were exposed to the extracts for 1day. Polymers Bio 1 to Bio 5 were prepared by solvent casting, Bio 6 to Bio 9 by photopolymerization of the monomers at wavelengths of 400-500nm in the presence of a suitable photoinitiation system. RESULTS: Bio 1, Bio 3, Bio 4, Bio 5, and Bio 7 showed moderate to excellent cytocompatibility for both HGFs and osteoblasts in viability tests. Together with the results of the cytotoxicity assays, four of the nine tested polymers were considered cytocompatible: Bio 1 (poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate; PVB)), Bio 4 and Bio 5 (functionalized oligolactones), and, to a limited degree, Bio 7 (urethane methacrylate). Except for Bio 7, the cytocompatible polymers showed intermediate water contact angles (74-85°) and therefore moderate to low hydrophilicity. SIGNIFICANCE: The non-cross-linked polymers Bio 1, Bio 4, or Bio 5, and the photopolymerized polymeric network Bio 7 display good/excellent cytocompatibility and are therefore potential candidates for tissue engineering in alveolar bone substitution.


Assuntos
Perda do Osso Alveolar/terapia , Materiais Biocompatíveis/farmacologia , Regeneração Óssea/fisiologia , Substitutos Ósseos/farmacologia , Gengiva/citologia , Polímeros/química , Materiais Biocompatíveis/síntese química , Substitutos Ósseos/síntese química , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/citologia , Humanos , Osteoblastos/citologia , Engenharia Tecidual/métodos
20.
Biotechnol J ; 6(4): 392-5, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21381207

RESUMO

The glycoprotein hormone equine chorionic gonadotropin (eCG) is a commercial product used in animal breeding as well as in veterinary medicine. The current state of the art for the purification of eCG from serum is pH fractionation with metaphosphoric acid, two ethanol precipitation steps as well as dialysis followed by fixed-bed chromatography. Two simplified processes, including the use of magnetic microsorbents for the purification of eCG have been developed. The processes reduce or even omit the use of organic solvents and the required solid-liquid separation steps, thus making them potential candidates for a first commercial application of magnetic beads in bioprocessing.


Assuntos
Gonadotropina Coriônica/sangue , Gonadotropina Coriônica/isolamento & purificação , Magnetismo , Absorção , Animais , Cavalos
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