RESUMO
Parenteral administration is one of the most commonly used drug delivery routes for nanoparticle-based dosage forms, such as lipid-based and polymeric nanoparticles. For the treatment of various diseases, parenteral administration include intravenous, subcutaneous, and intramuscular route. In drug development phase, multiparameter strategy with a focus on drug physicochemical properties and the specificity of the administration route is required. Nanoparticle properties in terms of size and targeted delivery, among others, are able to surpass many drawbacks of conventional dosage forms, but these unique properties can be a bottleneck for approval by regulatory authorities. Quality by Design (QbD) approach has been widely utilized in development of parenteral nanoparticle-based dosage forms. It fosters knowledge of product and process quality by involving sound scientific data and risk assessment strategies. A full and comprehensive investigation into the state of implementation and applications of the QbD approach in these complex drug products can highlight the gaps and challenges. In this review, the analysis of critical attributes and Design of Experiment (DoE) approach in different nanoparticulate systems, together with the proper utilization of Process Analytical Technology (PAT) applications are described. The essential of QbD approach for the design and development of nanoparticle-based dosage forms for delivery via parenteral routes is discussed thoroughly.
Assuntos
Nanopartículas , Nanopartículas/química , Humanos , Animais , Sistemas de Liberação de Medicamentos/métodos , Infusões Parenterais , Formas de Dosagem , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/químicaRESUMO
BACKGROUND: Assessing advanced life support (ALS) competence requires validated instruments. Existing instruments include aspects of technical skills (TS), non-technical skills (NTS) or both, but one instrument for detailed assessment that suits all resuscitation situations is lacking. This study aimed to develop an instrument for the evaluation of the overall ALS performance of the whole team. METHODS: This instrument development study had four phases. First, we reviewed literature and resuscitation guidelines to explore items to include in the instrument. Thereafter, we interviewed resuscitation team professionals (n = 66), using the critical incident technique, to determine possible additional aspects associated with the performance of ALS. Second, we developed an instrument based on the findings. Third, we used an expert panel (n = 20) to assess the validity of the developed instrument. Finally, we revised the instrument based on the experts' comments and tested it with six experts who evaluated 22 video recorded resuscitations. RESULTS: The final version of the developed instrument had 69 items divided into adherence to guidelines (28 items), clinical decision-making (5 items), workload management (12 items), team behaviour (8 items), information management (6 items), patient integrity and consideration of laymen (4 items) and work routines (6 items). The Cronbach's α values were good, and strong correlations between the overall performance and the instrument were observed. CONCLUSION: The instrument may be useful for detailed assessment of the team's overall performance, but the numerous items make the use demanding. The instrument is still under development, and more research is needed to determine its psychometric properties.
Assuntos
Suporte Vital Cardíaco Avançado/normas , Competência Clínica/normas , Tomada de Decisão Clínica , Fidelidade a Diretrizes , Guias como Assunto , Humanos , Equipe de Assistência ao Paciente , Psicometria , Reprodutibilidade dos Testes , Ressuscitação/instrumentação , Análise e Desempenho de Tarefas , Carga de TrabalhoRESUMO
This study reports the potential of different polymers and polymer incorporation methods to inhibit crystallisation and maintain supersaturation of amorphous indomethacin (IND) in aqueous suspensions during storage. Three different polymers (poly(vinyl pyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) and Soluplus® (SP)) were used and included in the suspensions either as a solid dispersion (SD) with IND or dissolved in the suspension medium prior to the addition of amorphous IND. The total concentrations of both IND and the polymer in the suspensions were kept the same for both methods of polymer incorporation. All the polymers (with both incorporation methods) inhibited crystallisation of the amorphous IND. The SDs were better than the predissolved polymer solutions at inhibiting crystallisation. The SDs were also better at maintaining drug supersaturation. SP showed a higher IND crystallisation inhibition and supersaturation potential than the other polymers. However, this depended on the method of addition. IND in SD with SP did not crystallise, nor did the SD generate any drug supersaturation, whereas IND in the corresponding predissolved SP solution crystallised (into the recently characterised η polymorphic form of the drug) but also led to a more than 20-fold higher IND solution concentration than that observed for crystalline IND. The ranking of the polymers with respect to crystallisation inhibition potential in SDs was SPâ«PVP>HPMC. Overall, this study showed that both polymer type and polymer incorporation method strongly impact amorphous form stability and drug supersaturation in aqueous suspensions.
Assuntos
Derivados da Hipromelose/química , Indometacina/química , Polietilenoglicóis/química , Polivinil/química , Povidona/química , Tecnologia Farmacêutica/métodos , Cristalização , Composição de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Difração de Pó , Solubilidade , Soluções , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Neuronal ceroid lipofuscinosis (NCL) diseases consist of a group of genetically inherited neurodegenerative disorders that share common symptoms such as seizures, psychomotor retardation, blindness, and premature death. Although gene defects behind the NCL diseases are well characterized, very little is known how these defects affect normal development of the brain and cause the pathology of the disease. To obtain understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN2, CLN3 and CLN5 genes was investigated in developing mouse brain. The relationship between the expression pattern and the developmental stage of the brain showed that these genes are co-expressed spatially and temporally during brain development. Throughout the development strong expression of the three mRNAs was detected in germinal epithelium and in ventricle regions, hippocampus and cerebellum, all representing regions that are known to be associated with the formation of new neurons. More specifically, RT-PCR studies on developing mouse cortices revealed that the CLN genes were temporally co-expressed in the neural progenitor cells together with known stem cell markers. This suggested that CLN2, CLN3 and CLN5 genes may play an important role in early embryonal neurogenesis.
Assuntos
Aminopeptidases/biossíntese , Encéfalo/embriologia , Dipeptidil Peptidases e Tripeptidil Peptidases/biossíntese , Glicoproteínas de Membrana/biossíntese , Chaperonas Moleculares/biossíntese , Células-Tronco Neurais/metabolismo , Serina Proteases/biossíntese , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Imuno-Histoquímica , Hibridização In Situ , Proteínas de Membrana Lisossomal , Camundongos , Camundongos Endogâmicos C57BL , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma , Tripeptidil-Peptidase 1RESUMO
Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.
Assuntos
Doença Celíaca/genética , Doença Celíaca/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Adulto , Estudos de Casos e Controles , Criança , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Finlândia , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , SuéciaRESUMO
Personality can be thought of as a set of characteristics that influence people's thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in 10 discovery samples (17,375 adults) and five in silico replication samples (3294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data of ≈ 2.4M single-nucleotide polymorphisms (SNPs; directly typed and imputed using HapMap data) were available. In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P=2.8 × 10(-8) and 3.1 × 10(-8)) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P=4.9 × 10(-8)). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.
Assuntos
Estudo de Associação Genômica Ampla , Personalidade/genética , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/fisiologia , Adulto , Idoso , Austrália , Cromossomos Humanos/genética , Simulação por Computador , Europa (Continente)/etnologia , Comportamento Exploratório , Feminino , Genótipo , Humanos , Katanina , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Inventário de Personalidade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos de Amostragem , Estados Unidos , População Branca/genéticaRESUMO
In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.
Assuntos
Envelhecimento/genética , Longevidade/genética , Seleção de Pacientes , Projetos de Pesquisa , Idoso , Idoso de 80 Anos ou mais , Cognição , Europa (Continente)/epidemiologia , Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 16 , Variações do Número de Cópias de DNA , Esquizofrenia/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Valores de Referência , Duplicações Segmentares Genômicas/genética , Deleção de Sequência/genética , Adulto JovemRESUMO
Hostility is a multidimensional personality trait with changing expression over the life course. We performed a genome-wide association study (GWAS) of the components of hostility in a population-based sample of Finnish men and women for whom a total of 2.5 million single-nucleotide polymorphisms (SNPs) were available through direct or in silico genotyping. Hostility dimensions (anger, cynicism and paranoia) were assessed at four time points over a 15-year interval (age range 15-30 years at phase 1 and 30-45 years at phase 4) in 982-1780 participants depending on the hostility measure. Few promising areas from chromosome 14 at 99 cM (top SNPs rs3783337, rs7158754, rs3783332, rs2181102, rs7159195, rs11160570, rs941898, P values <3.9 × 10(-8) with nearest gene Enah/Vasp-like (EVL)) were found suggestively to be related to paranoia and from chromosome 7 at 86 cM (top SNPs rs802047, rs802028, rs802030, rs802026, rs802036, rs802025, rs802024, rs802032, rs802049, rs802051, P values <6.9 × 10(-7) with nearest gene CROT (carnitine O-octanoyltransferase)) to cynicism, respectively. Some shared suggestive genetic influence for both paranoia and cynicism was also found from chromosome 17 at 2.8 cM (SNPs rs12936442, rs894664, rs6502671, rs7216028) and chromosome 22 at 43 cM (SNPs rs7510759, rs7510924, rs7290560), with nearest genes RAP1 GTPase activating protein 2 (RAP1GAP2) and KIAA1644, respectively. These suggestive associations did not replicate across all measurement times, which warrants further study on these SNPs in other populations.
Assuntos
Cromossomos Humanos/genética , Estudo de Associação Genômica Ampla/métodos , Hostilidade , Personalidade/genética , Adolescente , Adulto , Feminino , Finlândia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica , Adulto JovemRESUMO
AIMS: The aim of the study was to explore the validity of registry-based diagnoses of autism in Finland using the Autism Diagnostic Interview - Revised (ADI-R). This study was designed for the Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FIPS-A), an ongoing research project where registry-based diagnoses will be used for epidemiological studies. METHODS: In this small pilot study, a clinical sample of 95 subjects diagnosed with childhood autism or pervasive developmental disorder/pervasive developmental disorder - not otherwise specified (PDD/PDD-NOS) or Asperger's syndrome according to the Finnish Hospital Discharge Register (FHDR) was gathered nationwide. A small control group consisting of siblings without any registered diagnoses of those being examined was also included in the study. Diagnoses were further re-evaluated by interviewing parents with the ADI-R. RESULTS: The mean scores of autistic subjects clearly exceeded cut-off limits for autism on all three ADI-R domains and 96% of the subjects with registered diagnosis of childhood autism fulfilled the criteria based on the instrument as well. CONCLUSION: These results suggest that the validity of Finnish registry-based diagnoses of childhood autism can be considered good. Our findings lay important groundwork for further population- based studies of the aetiology of autism.
Assuntos
Transtorno Autístico/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Entrevista Psicológica , Síndrome de Asperger/diagnóstico , Síndrome de Asperger/epidemiologia , Transtorno Autístico/epidemiologia , Estudos de Casos e Controles , Criança , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Finlândia , Humanos , Projetos Piloto , Sistema de Registros/estatística & dados numéricos , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: To identify common loci and potential genetic variants affecting body mass index (BMI, kg m(-2)) in study populations originating from Europe. DESIGN: We combined genome-wide linkage scans of six cohorts from Australia, Denmark, Finland, the Netherlands, Sweden and the United Kingdom with an approximately 10-cM microsatellite marker map. Variance components linkage analysis was carried out with age, sex and country of origin as covariates. SUBJECTS: The GenomEUtwin consortium consists of twin cohorts from eight countries (Australia, Denmark, the Netherlands, Finland, Italy, Norway, Sweden and the United Kingdom) with a total data collection of more than 500,000 monozygotic and dizygotic (DZ) twin pairs. Variance due to early-life events and the environment is reduced within twin pairs, which makes DZ pairs highly valuable for linkage studies of complex traits. This study totaled 4401 European-originated twin families (10,535 individuals) from six countries (Australia, Denmark, the Netherlands, Finland, Sweden and the United Kingdom). RESULTS: We found suggestive evidence for a quantitative trait locus on 3q29 and 7q36 in the combined sample of DZ twins (multipoint logarithm of odds score (MLOD) 2.6 and 2.4, respectively). Two individual cohorts showed strong evidence independently for three additional loci: 16q23 (MLOD=3.7) and 2p24 (MLOD=3.4) in the Dutch cohort and 20q13 (MLOD=3.2) in the Finnish cohort. CONCLUSION: Linkage analysis of the combined data in this large twin cohort study provided evidence for suggestive linkage to BMI. In addition, two cohorts independently provided significant evidence of linkage to three new loci. The results of our study suggest a smaller environmental variance between DZ twins than full siblings, with a corresponding increase in heritability for BMI as well as an increase in linkage signal in well-replicated regions. The results are consistent with the possibility of locus heterogeneity for some genomic regions, and indicate a lack of major common quantitative trait locus variants affecting BMI in European populations.
Assuntos
Índice de Massa Corporal , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Ligação Genética/genética , Locos de Características Quantitativas/genética , Gêmeos Dizigóticos/genética , Adulto , Idoso , Estudos de Coortes , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Gêmeos/genética , População Branca/genéticaRESUMO
BACKGROUND: Clinical cone-beam computed tomography (CBCT), used in diagnostics of dental and maxillofacial radiology for almost 10 years, allows three-dimensional (3D) imaging of a focused area, with reasonable radiation dose. PURPOSE: To clarify the applicability of CBCT in imaging of the temporal bone. MATERIAL AND METHODS: We imaged cadaver temporal bones, one non-operated and five postmortem operated, with CBCT to evaluate the accuracy of this method in showing clinically important landmarks and the positions of middle-ear implants. In addition, to clarify the imaging protocols for the best possible result, we conducted a contrast-to-noise ratio (CNR) analysis by imaging a specially built phantom insert with different protocols. RESULTS: For all the temporal bones, image quality was good and of diagnostic value, and the surgical landmarks as well as positions and details of the implants could be accurately observed. Based on measurements conducted with the phantom, the best possible clarity of the images with the machine used (3D Accuitomo; Morita Co., Kyoto, Japan) was achieved with a tube voltage of 80 kVp and a current of 4 mA. CONCLUSION: Cone-beam CT is a promising new method for otologic imaging, based on its accuracy and relatively low radiation exposure per investigation.
Assuntos
Tomografia Computadorizada de Feixe Cônico/métodos , Osso Temporal/diagnóstico por imagem , Cadáver , Humanos , Imageamento Tridimensional/métodos , Imagens de Fantasmas , Reprodutibilidade dos TestesRESUMO
A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.
Assuntos
Cromossomos Humanos/genética , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Escore Lod , Masculino , LinhagemRESUMO
BACKGROUND: Restless legs syndrome (RLS) is associated with common variants in three intronic and intergenic regions in MEIS1, BTBD9, and MAP2K5/LBXCOR1 on chromosomes 2p, 6p and 15q. METHODS: Our study investigated these variants in 649 RLS patients and 1230 controls from the Czech Republic (290 cases and 450 controls), Austria (269 cases and 611 controls) and Finland (90 cases and 169 controls). Ten single nucleotide polymorphisms (SNPs) within the three genomic regions were selected according to the results of previous genome-wide scans. Samples were genotyped using Sequenom platforms. RESULTS: We replicated associations for all loci in the combined samples set (rs2300478 in MEIS1, p = 1.26 x 10(-5), odds ratio (OR) = 1.47, rs3923809 in BTBD9, p = 4.11 x 10(-5), OR = 1.58 and rs6494696 in MAP2K5/LBXCOR1, p = 0.04764, OR = 1.27). Analysing only familial cases against all controls, all three loci were significantly associated. Using sporadic cases only, we could confirm the association only with BTBD9. CONCLUSION: Our study shows that variants in these three loci confer consistent disease risks in patients of European descent. Among the known loci, BTBD9 seems to be the most consistent in its effect on RLS across populations and is also most independent of familial clustering.
Assuntos
Polimorfismo de Nucleotídeo Único , Síndrome das Pernas Inquietas/genética , Adulto , Idoso , Áustria , Proteínas Correpressoras , República Tcheca , Feminino , Finlândia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Proteínas de Homeodomínio/genética , Humanos , MAP Quinase Quinase 5/genética , Masculino , Pessoa de Meia-Idade , Proteína Meis1 , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso , Razão de Chances , Proteínas Repressoras/genética , Fatores de Transcrição/genéticaAssuntos
Transtorno Bipolar/genética , Saúde da Família , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Estudos de Coortes , Diacilglicerol Quinase , Proteína do Grupo de Complementação N da Anemia de Fanconi , Finlândia , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana/genética , Proteínas Nucleares , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas , Receptores de Superfície Celular , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Proteínas Supressoras de TumorRESUMO
Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73+/-95% confidence interval (CI) 1.42-5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64+/-95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27+/-95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.
Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Frequência do Gene , Genótipo , Humanos , Cooperação Internacional , Masculino , Testes Neuropsicológicos , Razão de Chances , Escalas de Graduação Psiquiátrica , Fatores SexuaisRESUMO
OBJECTIVES: QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample. METHODS: We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. RESULTS: The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QT(Nc) interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P=4.7 x 10(-5)], KCNH2 K897T [-2.6 ms (SE 0.5) or -0.14 SD, P=2.1 x 10(-7)] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P=3.2 x 10(-24)] under additive models. CONCLUSIONS: We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Variação Genética/genética , Síndrome do QT Longo/genética , Polimorfismo de Nucleotídeo Único , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go/genética , Feminino , Finlândia/epidemiologia , Genótipo , Humanos , Síndrome do QT Longo/epidemiologia , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
Amorphous drugs have a higher kinetic solubility and dissolution rate than their crystalline counterparts. However, this advantage is lost if the amorphous form converts to the stable crystalline form during the dissolution as the dissolution rate will gradually change to that of the crystalline form. The purpose of this study was to use in situ Raman spectroscopy in combination with either partial least squares discriminant analysis (PLS-DA) or partial least squares (PLS) regression analysis to monitor as well as quantify the solid-phase transitions that take place during the dissolution of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissolution rate was higher from amorphous IMC compared to the crystalline alpha- and gamma-forms. However, the dissolution rate started to slow down during the experiment. In situ Raman analysis verified that at that time point the sample started to crystallize to the alpha-form. Amorphous CBZ instantly started to crystallize upon contact with the dissolution medium. The transition from the amorphous form to CBZ dihydrate appears to go through the anhydrate form I. Based on the PLS analysis the amount of form I formed in the sample during the dissolution affected the dissolution rate. Raman spectroscopy combined with PLS-DA was also more sensitive to the solid-state changes than X-ray powder diffraction (XRPD) and was able to detect changes in the solid-state that could not be detected with XRPD.