RESUMO
The objectives of this study were to assess the effect of 2 different premilking stimulation regimens, with and without a latency period between tactile stimulation and the attachment of the milking unit, on the teat tissue condition and milking performance of dairy cows. In a randomized controlled crossover study, 145 Holstein cows milked 3 times daily were assigned to treatment (TRT) or control (CON) groups. Premilking udder preparation for the TRT group consisted of the application of a latency period resulting in a preparation lag time of 90 s. The only difference in the premilking udder preparation of the CON group was the absence of latency period; the milking unit was attached immediately after completion of the tactile stimulation. The average duration of total tactile stimulation in TRT and CON group was 8 ± 2 and 9 ± 2 s, respectively. The study lasted for 14 d and was split into 2 periods, each consisting of a 2-d adjustment period followed by 5 d of data collection. We assessed machine milking-induced short-term changes to the teat tissue by palpation and visual inspection postmilking. Electronic on-farm milk meters were used to assess milking characteristics (milk yield [kg/milking session], machine-on time [s], 2-min milk yield [kg], and duration of low milk flow rate [s]). Generalized linear mixed models were used to analyze the effect of treatment on the outcome variables. The odds of machine milking-induced short-term changes to the teat tissue were lower for cows that received a 90-s preparation lag time (TRT cows) compared with cows in the CON group (odds ratio [95% confidence interval; 95% CI] = 0.13 [0.08-0.20]). The least squares means (95% CI) values of cows in the TRT and CON groups were 15.4 (14.9-15.9) and 15.3 (14.8-15.8) kg, respectively, for milk yield, and 246 (239-253) and 253 (247-260) s for machine-on time. The 2-min milk yield was higher for the TRT compared with CON group cows at all the parity levels. The 2-min milk yields of animals in lactation 1, 2, and ≥3 were 5.7, 5.7, and 6.5 kg, respectively, in the TRT group and 4.6, 5.0, and 5.9 kg in the CON group. The TRT cows spent less time in low milk flow rate compared with CON cows at all parity levels. The durations of low milk flow rate of cows in lactation 1, 2, and ≥3 in the TRT group were 19, 17 and 13 s, respectively, and those in the CON group were 31, 22, and 15 s. In this study, cows that received a latency period, and thus were subjected to a 90-s preparation lag time had lower odds of exhibiting short-term changes to the teat tissue after machine milking, shorter machine-on time, higher 2-min milk yields, and lower durations of low milk flow rates. We conclude that consideration of latency period leading to a 90-s preparation lag time in the premilking stimulation regimen facilitated cows' milk-ejection reflex. This latency period can alleviate the adverse effects of vacuum-induced forces on teat tissue during machine milking, improve udder health, and promote animal well-being.
Assuntos
Glândulas Mamárias Animais , Leite , Feminino , Gravidez , Bovinos , Animais , Estudos Cross-Over , Lactação , Coleta de DadosRESUMO
PURPOSE: The purpose of this article is (1) to investigate which medicines are prescribed and dispensed to women the first 6 months postpartum, (2) to identify medicines dispensed postpartum but not recommended during breastfeeding, and (3) to find medicines commonly dispensed postpartum, but not currently included in Janusmed Breastfeeding. METHODS: In this register-based cohort study covering births between January 2017 and August 2019, the Swedish Medical Birth Register (MBR), the Prescribed Drug Register, and Janusmed Breastfeeding were linked to identify medicines dispensed to women during the first 6 months postpartum, and how they are covered and classified in Janusmed Breastfeeding. RESULTS: During the first 6 months postpartum, 66% of women purchased at least one prescription medicine from the pharmacy. The most common medicines were contraceptive agents, analgesics, antibiotics, and glucocorticoids. A third of the 30 most commonly dispensed medicines have no information available about the safety of use in breastfeeding. The most dispensed medicines, where the database advises against use in breastfeeding, included several antitussive agents, a local anaesthetic, and several gestagens. The most commonly dispensed medicines not covered by the Janusmed Breastfeeding were medicines for dry eyes, for assisted reproduction, and HIV. CONCLUSION: Prescribed medicines compatible with breastfeeding are more common during the first 6 months postpartum than medicines not compatible with breastfeeding, but medicines which lack evidence for safety in breastfeeding are still commonly used.
Assuntos
Aleitamento Materno , Período Pós-Parto , Feminino , Humanos , Suécia , Estudos de Coortes , ProgestinasRESUMO
AIM: Knowledge on the neurodevelopmental and physical function in children with vertebral defects, anorectal malformations, cardiac defects, tracheo-oesophageal fistula, renal and limb malformations (VACTERL) is scarce. We evaluated Swedish preschool children with VACTERL and identified whether they would need extra support in school. METHODS: From 2015 to 2017, we recruited children aged 5-7 with VACTERL association from the paediatric surgical centre at the University Children's Hospital at Uppsala. Neurodevelopmental function was assessed by age-appropriate intelligence and visual and auditory attention tests, and the children's behaviour and attention were observed by an experienced psychologist. Physical function was evaluated through parental interviews and examinations. Data on patient characteristics, including any surgery and anaesthesia, were extracted from medical records. RESULTS: Of the 13 eligible families, 10 agreed to participate. Intelligence was within the normal range for all children, but attention difficulties were found in eight of the children, requiring adjustments at school, and two of these were later diagnosed with attention deficit hyperactivity disorder. All children had physical dysfunctions that affected their daily nutrition, bowel or bladder functions. CONCLUSION: Attention difficulties and physical dysfunction were common in Swedish preschool children aged 5-7 with VACTERL and they would need support and adjustments when they started school.
Assuntos
Cardiopatias Congênitas , Deformidades Congênitas dos Membros , Canal Anal/anormalidades , Criança , Pré-Escolar , Esôfago/anormalidades , Cardiopatias Congênitas/complicações , Humanos , Rim/anormalidades , Deformidades Congênitas dos Membros/epidemiologia , Coluna Vertebral/anormalidades , Traqueia/anormalidadesRESUMO
AIMS: To determine the prevalence of unidentified diabetes mellitus among 67-year-olds in Denmark participating in a screening programme focusing on cardiovascular disease and diabetes, and to describe glycaemic levels in individuals according to point-of-care HbA1c combined with self-reported diabetes status. METHODS: In this cross-sectional, retrospective, population-based study, all people aged 67 years living in the Viborg municipality were invited to take part in the Viborg Inter-sectorial Screening Programme (VISP), which focuses on cardiovascular disease and diabetes. The VISP study was initiated in August 2014 and is ongoing. During the first 2 years of the programme, we stratified participants into groups based on their self-reported diabetes status and a single HbA1c measurement. RESULTS: A total of 1802 individuals were invited to participate, and 1501 consented, seven of whom were excluded because of missing data (HbA1c or diabetes status), resulting in an 82.9% participation rate (n=1494). Among those reporting not to have diabetes, 3.3% (n=45) had an HbA1c level ≥48 mmol/mol (6.5%). In the same group, 16.7% (n=226) had an HbA1c level of 41-48 mmol/mol (5.9-6.5%). Among those self-reporting the presence of diabetes, 30.1% (n=43) had an HbA1c level ≥58 mmol/mol (7.5%). CONCLUSIONS: The prevalence of unidentified diabetes was 3.3% based on a single HbA1c measurement. Furthermore, 16.7% of those reporting not to have diabetes had an HbA1c level of 41-48 mmol/mol (5.9-6.5%), representing a subgroup with an increased risk of developing diabetes. Among those with self-reported diabetes, 30.1% had an HbA1c level ≥58 mmol/mol (7.5%) and 6.3% had a level >74 mmol/mol (8.9%).
RESUMO
PURPOSE: We assessed the value of standard biochemical coagulation parameters in predicting bleeding, thrombosis and mortality in adult Intensive Care Unit (ICU) patients with haematological malignancies. METHODS: We screened all patients with acute leukaemia and myelodysplastic syndrome admitted to a university hospital ICU during 2008-2012. Data were obtained from the clinical chemistry laboratory database and patient files. We graded bleeding according to the World Health Organisation (WHO)-system within 24-h, within 5-days and during the whole ICU stay. We analysed the predictive values of laboratory parameters using multiple logistic regression and receiver operator characteristics (ROC) curves. As we previously have established that platelet count at admission was associated with bleeding, we focused on International Normalised Ratio (INR), activated pro-thrombin time (APTT), anti-thrombin, D-dimer and fibrinogen, and markers of infection (C-reactive protein, pro-calcitonin), kidney function (creatinine) and tissue damage (lactate dehydrogenase (LDH)). RESULTS: We included 116 patients; 66 (57%) had at least one bleeding episode and 11 (9%) patients had at least one thrombotic event. The differences in coagulation values when bleeding compared to baseline values were minor. INR was the only variable we found associated with subsequent bleeding within 24 h from admission to ICU (odds ratio 2.91, 95% CI: 1.01-8.43, P = 0.048). ROC analyses did not show predictive value of any of the other variables with regards to bleeding and none of the variables were associated with thrombosis in adjusted analyses. Increased levels of LDH at admission were associated with increased 7-day and 30-day mortality. CONCLUSIONS: Increased INR at admission was associated with a higher rate of bleeding in ICU patients with haematological malignancies. No other biochemical coagulation or other parameter had any association with bleeding, thrombosis or mortality except increased LDH, which at ICU admission was associated with increased 30-day mortality.
Assuntos
Testes de Coagulação Sanguínea , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/complicações , Hemorragia/diagnóstico , Trombose/diagnóstico , Idoso , Coagulação Sanguínea , Cuidados Críticos , Feminino , Neoplasias Hematológicas/mortalidade , Hemorragia/etiologia , Humanos , Coeficiente Internacional Normatizado , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Pacientes , Contagem de Plaquetas , Valor Preditivo dos Testes , Curva ROC , Trombose/etiologiaRESUMO
BACKGROUND: Autoantibodies, in particular those against aquaporin-4 and myelin-oligodendrocyte glycoprotein (MOG), aid as biomarkers in the differential diagnosis of demyelination. Here, we report on discovery of autoantibodies against flotillin in patients with multiple sclerosis (MS). METHODS: The target antigen was identified by histo-immunoprecipitation using the patients' sera and cryosections of rat or pig cerebellum combined with mass spectrometrical analysis. Correct identification was ascertained by indirect immunofluorescence and neutralization tests using the target antigens recombinantly expressed in HEK293 cells. RESULTS: Serum and CSF of the index patient produced a fine-granular IgG indirect immunofluorescence staining of the hippocampal and cerebellar molecular layers. Flotillin-1 and flotillin-2 were identified as target autoantigens. They also reacted with recombinant human flotillin-1/2 co-expressed in HEK293 cells, but not with the individual flotillins in fixed- and live-cell assays. Moreover, neutralization using flotillin-1/2, but not the single flotillins, abolished the tissue reactivity of patient serum. Screening of 521 patients, for whom anti-aquaporin-4 testing was requested and negative, revealed 8 additional patients with anti-flotillin-1/2 autoantibodies. All eight were negative for anti-MOG. Six patients ex post fulfilled the revised McDonald criteria for MS. Vice versa, screening of 538 MS sera revealed anti-flotillin-1/2 autoantibodies in eight patients. The autoantibodies were not found in a cohort of 67 patients with other neural autoantibody-associated syndromes and in 444 healthy blood donors. CONCLUSIONS: Autoantibodies against the flotillin-1/2 heterocomplex, a peripheral membrane protein that is involved in axon outgrowth and regeneration of the optic nerve, are present in 1-2% of patients with bona fide MS.
Assuntos
Autoanticorpos/metabolismo , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/metabolismo , Esclerose Múltipla/metabolismo , Adulto , Animais , Autoanticorpos/imunologia , Feminino , Células HEK293 , Humanos , Masculino , Microdomínios da Membrana/imunologia , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Ratos , SuínosRESUMO
BACKGROUND: In sudden, unexpected, non-traumatic death in young individuals, structural abnormalities of the heart are frequently identified at autopsy. However, the findings may be unspecific and cause of death may remain unclear. A significant proportion of these cases are most likely caused by inherited cardiac diseases, and the cases are categorized as sudden cardiac death (SCD). The purpose of this study was to explore the added diagnostic value of genetic testing by next-generation sequencing (NGS) of a broad gene panel, as a supplement to the traditional forensic investigation in cases with non-diagnostic structural abnormalities of the heart. METHODS AND RESULTS: We screened 72 suspected SCD cases (<50 years) using the HaloPlex Target Enrichment System (Agilent) and NGS (Illumina MiSeq) for 100 genes previously associated with inherited cardiomyopathies and channelopathies. Fifty-two cases had non-diagnostic structural cardiac abnormalities and 20 cases, diagnosed with a cardiomyopathy post-mortem (ARVC = 14, HCM = 6), served as comparators. Fifteen (29%) of the deceased individuals with non-diagnostic findings had variants with likely functional effects based on conservation, computational prediction, allele-frequency and supportive literature. The corresponding frequency in deceased individuals with cardiomyopathies was 35% (p = 0.8). CONCLUSION: The broad genetic screening revealed variants with likely functional effects at similar high rates, i.e. in 29 and 35% of the suspected SCD cases with non-diagnostic and diagnostic cardiac abnormalities, respectively. Although the interpretation of broad NGS screening is challenging, it can support the forensic investigation and help the cardiologist's decision to offer counselling and clinical evaluation to relatives of young SCD victims.
Assuntos
Morte Súbita Cardíaca/etiologia , Genética Forense , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Cardiomiopatia Hipertrófica/genética , Feminino , Fibrose , Patologia Legal , Humanos , Hipertrofia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Direita/patologia , Masculino , Miocárdio/patologia , Adulto JovemRESUMO
Sudden cardiac death (SCD) is responsible for a large proportion of sudden deaths in young individuals. In forensic medicine, many cases remain unexplained after routine postmortem autopsy and conventional investigations. These cases are called sudden unexplained deaths (SUD). Genetic testing has been suggested useful in forensic medicine, although in general with a significantly lower success rate compared to the clinical setting. The purpose of the study was to estimate the frequency of pathogenic variants in the genes most frequently associated with SCD in SUD cases and compare the frequency to that in patients with inherited cardiac channelopathies. Fifteen forensic SUD cases and 29 patients with channelopathies were investigated. DNA from 34 of the genes most frequently associated with SCD were captured using NimbleGen SeqCap EZ library build and were sequenced with next-generation sequencing (NGS) on an Illumina MiSeq. Likely pathogenic variants were identified in three out of 15 (20%) forensic SUD cases compared to 12 out of 29 (41%) patients with channelopathies. The difference was not statistically significant (p = 0.1). Additionally, two larger deletions of entire exons were identified in two of the patients (7%). The frequency of likely pathogenic variants was >2-fold higher in the clinical setting as compared to SUD cases. However, the demonstration of likely pathogenic variants in three out of 15 forensic SUD cases indicates that NGS investigations will contribute to the clinical investigations. Hence, this has the potential to increase the diagnostic rate significantly in the forensic as well as in the clinical setting.
Assuntos
Canalopatias/genética , Morte Súbita Cardíaca/etiologia , Sequenciamento de Nucleotídeos em Larga Escala , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genética Forense , Humanos , Mutação INDEL , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Adulto JovemRESUMO
The human leukocyte antigen (HLA) class Ib molecule, HLA-G, has gained increased attention because of its assumed important role in immune regulation. The HLA-G protein exists in several soluble isoforms. Most important are the actively secreted HLA-G5 full-length isoform generated by alternative splicing retaining intron 4 with a premature stop codon, and the cleavage of full-length membrane-bound HLA-G1 from the cell surface, so-called soluble HLA-G1 (sHLA-G1). A specific and sensitive immunoassay for measurements of soluble HLA-G is mandatory for conceivable routine testing and research projects. We report a novel method, a competitive immunoassay, for measuring HLA-G5/sHLA-G1 in biological fluids. The sHLA-G immunoassay is based upon a competitive enzyme-linked immunosorbent assay (ELISA) principle. It includes a recombinant sHLA-G1 protein in complex with ß2-microglobulin and a peptide as a standard, biotinylated recombinant sHLA-G1 as an indicator, and the MEM-G/9 anti-HLA-G monoclonal antibody (mAb) as the capture antibody. The specificity and sensitivity of the assay were evaluated. Testing with different recombinant HLA class I proteins and different anti-HLA class I mAbs showed that the sHLA-G immunoassay was highly specific. Optimal combinations of competitor sHLA-G1 and capture mAb concentrations were determined. Two versions of the assay were tested. One with a relatively wide dynamic range from 3.1 to 100.0 ng/ml, and another more sensitive version ranging from 1.6 to 12.5 ng/ml. An intra-assay coefficient of variation (CV) of 15.5% at 88 ng/ml and an inter-assay CV of 23.1% at 39 ng/ml were determined. An assay based on the competitive sHLA-G ELISA may be important for measurements of sHLA-G proteins in several conditions: assisted reproduction, organ transplantation, cancer, and certain pregnancy complications, both in research studies and possibly in the future also for clinical routine use.
Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Antígenos HLA-G/sangue , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos/imunologia , Biotinilação , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/química , Antígenos HLA-G/imunologia , Humanos , Proteínas Recombinantes/imunologia , Padrões de Referência , Sensibilidade e Especificidade , SolubilidadeRESUMO
The widely used antipsychotic drug, olanzapine (OLA) shows large interindividual variability in metabolic clearance. Although the role of the enzymes CYP1A2, CYP2D6 and UGT1A4 has been extensively explored, little is known about the in vivo role of flavin-containing monooxygenases (FMOs) catalyzing the N-oxidation of OLA in vitro. We investigated the influence of FMO1 and 3 polymorphisms on the steady state serum concentrations of OLA and its N-oxide metabolite in 379 patients. The upstream FMO1*6 was associated with increased dose-adjusted serum OLA concentrations (C/Ds; P=0.008), an effect further enhanced by FMO1rs7877C>T in smokers. The influence of FMO3 polymorphisms was limited to variability in OLA N-oxide. Homozygous carriers of FMO3rs2266780A>G (p.E308G) displayed 50% lower C/D of OLA N-oxide compared with subjects homo- or heterozygous for the A-variant (P<0.003). Our data support the role of FMO3 in the N-oxidation of OLA and implicate for the first time the contribution of FMO1 and its functional *6 variant in OLA disposition.
Assuntos
Benzodiazepinas/sangue , Transtornos Mentais/tratamento farmacológico , Óxidos/sangue , Oxigenases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzodiazepinas/uso terapêutico , Feminino , Humanos , Masculino , Transtornos Mentais/sangue , Transtornos Mentais/genética , Pessoa de Meia-Idade , Olanzapina , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: Patients with cancer are often treated with glucocorticoids (gcs) as part of therapy, which may cause hyperglycemia. We sought to define the prevalence of, and risk factors for, hyperglycemia in this setting. METHODS: Adult patients taking gc as part of therapy protocols for primary brain tumour or metastasis, for lymphoma, or for bone marrow transplant (bmt) were screened with random glucometer measurements taken at least 3 hours after the last dose gcs. RESULTS: We screened 90 patients [44.4% women, 55.6% men; mean age: 59.6 years (range: 25-82 years); mean body mass index (bmi): 26.4 kg/m(2) (range: 15.8-45.3 kg/m(2))] receiving gc as part of cancer treatment. Mean total daily gc dose in the group was 238.5 mg (range: 30-1067 mg) hydrocortisone equivalents. Hyperglycemia (glucose ≥ 8.0 mmol/L) was found in 58.9% (53 of 90), and diabetes mellitus (dm)-range hyperglycemia (glucose ≥ 11.1 mmol/L) in 18.9% (17 of 90). The mean time from gc ingestion to glucometer testing was 5.5 hours (range: 3-20 hours). Presence of hyperglycemia did not correlate with traditional dm risk factors such as age, sex, bmi, and personal or family history of dm. A longer interval from gc dose to testing (p < 0.05), a higher gc dose (p = 0.04), and a shorter interval between the preceding meal and testing (p = 0.02) were risk factors for hyperglycemia in some patient groups. CONCLUSIONS: Glucocorticoid-induced hyperglycemia is common in patients undergoing cancer treatment and cannot be predicted by traditional risk factors for dm. We recommend that all cancer patients receiving gc be screened for hyperglycemia at least 4-6 hours after gc administration.
RESUMO
BACKGROUND AND OBJECTIVE: It is documented that low protein and amino-acid dietary intake is related to poorer cognitive health and increased risk of dementia. Degradation of the neuromodulatory pathways, (comprising the cholinergic, dopaminergic, serotoninergic and noradrenergic systems) is observed in neurodegenerative diseases and impairs the proper biosynthesis of key neuromodulators from micro-nutrients and amino acids. How these micro-nutrients are linked to neuromodulatory pathways in healthy adults is less studied. The Locus Coeruleus-Noradrenergic System (LC-NA) is the earliest subcortical structure affected in Alzheimer's disease, showing marked neurodegeneration, but is also sensitive for age-related changes. The LC-NA system is critical for supporting attention and cognitive control, functions that are enhanced both by tyrosine administration and chronic tyrosine intake. The purpose of this study was to 1) investigate whether the dietary intake of tyrosine, the key precursor for noradrenaline (NA), is related to LC signal intensity 2) whether LC mediates the reported association between tyrosine intake and higher cognitive performance (measured with Trail Making Test - TMT), and 3) whether LC signal intensity relates to an objective measure of brain maintenance (BrainPAD). METHODS: The analyses included 398 3T MRIs of healthy participants from the Berlin Aging Study II to investigate the relationship between LC signal intensity and habitual dietary tyrosine intake-daily average (HD-Tyr-IDA - measured with Food Frequency Questionnaire - FFQ). As a control procedure, the same analyses were repeated on other main seeds of the neuromodulators' subcortical system (Dorsal and Medial Raphe, Ventral Tegmental Area and Nucleus Basalis of Meynert). In the same way, the relationships between the five nuclei and BrainPAD were tested. RESULTS: Results show that HD-Tyr-IDA is positively associated with LC signal intensity. Similarly, LC disproportionally relates to better brain maintenance (BrainPAD). Mediation analyses reveal that only LC, relative to the other nuclei tested, mediates the relationship between HD-Tyr-IDA I and performance in the TMT and between HD-Tyr-IDA and BrainPAD. CONCLUSIONS: These findings provide the first evidence linking tyrosine intake with LC-NA system signal intensity and its correlation with neuropsychological performance. This study strengthens the role of diet for maintaining brain and cognitive health and supports the noradrenergic theory of cognitive reserve. Within this framework, adequate tyrosine intake might increase the resilience of LC-NA system functioning, by preventing degeneration and supporting noradrenergic metabolism required for LC function and neuropsychological performance.
Assuntos
Locus Cerúleo , Tirosina , Humanos , Locus Cerúleo/metabolismo , Tirosina/metabolismo , Substância Cinzenta/diagnóstico por imagem , Envelhecimento , Norepinefrina/metabolismo , Imageamento por Ressonância Magnética , Atenção , Dieta , Ingestão de Alimentos , Neurotransmissores/metabolismoRESUMO
The ß(2)-adrenergic receptor (ADRB2) is an important regulator of airway smooth muscle tone. We tested the hypothesis that three functional polymorphisms in the ADRB2 gene (Thr164Ile, Gly16Arg and Gln27Glu) are associated with reduced lung function, asthma or chronic obstructive pulmonary disease (COPD). We first genotyped 8,971 individuals from the Copenhagen City Heart Study for all three polymorphisms. To validate our findings, we genotyped an additional 53,777 individuals from the Copenhagen General Population Study for the Thr164Ile polymorphism. We identified 60,910 Thr164Ile noncarriers, 1,822 heterozygotes and 16 homozygotes. In the Copenhagen City Heart Study, the Thr164Ile genotype was associated with reduced forced expiratory volume in 1 s (FEV(1)) % predicted (trend p = 0.01) and FEV(1)/forced vital capacity (FVC) (p = 0.001): Thr164Ile heterozygotes had 3% and 2% reduced FEV(1) % pred and FEV(1)/FVC, respectively, compared with noncarriers. The odds ratio for COPD in Thr164Ile heterozygotes was 1.46 (95% CI 1.05-2.02). In the Copenhagen General Population Study, the Thr164 genotype associated with reduced FEV(1) % pred (p = 0.04) and FEV(1)/FVC (p < 0.001): Thr164Ile homozygotes and heterozygotes had 7% and 1% reduced FEV(1) % pred and 6% and 1% reduced FEV(1)/FVC, respectively, compared with noncarriers. The odds ratios for COPD in Thr164Ile homozygotes and heterozygotes were 4.53 (95% CI 1.54-13.3) and 1.07 (95% CI 0.92-1.25), respectively. Our results suggest that ADRB2 Thr164Ile is associated with reduced lung function and increased risk of COPD in the general population.
Assuntos
Asma/genética , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/genética , Receptores Adrenérgicos beta 2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/epidemiologia , Dinamarca/epidemiologia , Feminino , Frequência do Gene , Humanos , Incidência , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prevalência , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Adulto JovemRESUMO
OBJECTIVES: The ß(2) -adrenergic receptor (ADRB2) is located on smooth muscle cells and is an important regulator of smooth muscle tone. The Thr164Ile polymorphism (rs1800888) in the ADRB2 gene is rare but has profound functional consequences on receptor function and could cause lifelong elevated smooth muscle tone. We tested the hypothesis that Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of cardiovascular disease (CVD). SUBJECTS: A total of 66 750 individuals from two large Danish general population studies were genotyped, and 1943 Thr164Ile heterozygotes and 16 homozygotes were identified. RESULTS: Thr164Ile genotype was associated with increased systolic and diastolic blood pressure in women (trend: P = 0.04 and 0.02): systolic and diastolic blood pressure increased by 5% and 2%, respectively, in female homozygotes compared with female noncarriers. All female Thr164Ile homozygotes had hypertension compared with 58% of female heterozygotes and 54% of female noncarriers (chi-square: P = 0.001). Female Thr164Ile homozygotes and heterozygotes had odds ratios for ischaemic heart disease (IHD) of 2.93 (0.56-15.5) and 1.28 (1.03-1.61), respectively, compared with female noncarriers (trend: P = 0.007). These differences were not observed in men. Furthermore, Gly16Arg (rs1042713) and Gln27Glu (rs1042714) in the ADRB2 gene were not associated with blood pressure, hypertension or CVD either in the population overall or in women and men separately. CONCLUSIONS: ADRB2 Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of IHD amongst women in the general population. These findings, particularly for homozygotes, are novel.
Assuntos
Pressão Sanguínea/genética , Predisposição Genética para Doença/genética , Hipertensão/genética , Isquemia Miocárdica/genética , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 2/genética , Idoso , Estudos Transversais , Dinamarca , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético , Miócitos de Músculo Liso , Estudos Prospectivos , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
The surfactant protein (SP)-B gene may influence chronic obstructive pulmonary disease (COPD) and, thus, personalised medicine. We tested whether functional polymorphisms in SP-B (rs1130866 (1580T>C), rs2077079 (-18A>C) and rs3024791 (-384G>A)) associate with reduced lung function and risk of COPD in the general population. We genotyped 10,231 individuals from the general adult Danish population, and recorded spirometry and hospital admissions due to COPD. Because we previously found an association between the rare SP-B 121ins2 mutation and COPD among smokers, we stratified the analyses for smoking status. None of the individual SP-B genotypes or genotype combinations were associated with reduced forced expiratory volume in 1 s (FEV1) % predicted, forced vital capacity (FVC) % pred and FEV1/FVC overall or among smokers (p = 0.25-0.99). The odds ratio for spirometrically defined COPD did not differ from 1.0 for any of the SP-B genotypes or genotype combinations overall or among smokers (p = 0.17-0.78). Similar results were obtained for hospitalisation due to COPD (p = 0.07-0.93); we could exclude overall hazard ratios for heterozygotes of 1.18-1.21 and for homozygotes of 1.25-1.57 or larger for all three polymorphisms. In conclusion, the functional rs1130866, rs2077079 and rs3024791 polymorphisms in the SP-B gene are not associated with reduced lung function or risk of COPD, making it unlikely that these variants will be useful in personalised medicine.
Assuntos
Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/genética , Proteína B Associada a Surfactante Pulmonar/genética , Adulto , Idoso , Asma/genética , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Pulmão/metabolismo , Doenças Pulmonares Intersticiais/genética , Masculino , Pessoa de Meia-Idade , Mutação , Pneumonia/diagnóstico , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Testes de Função Respiratória , RiscoRESUMO
We tested the hypothesis that two well-characterised functional polymorphisms of the microsomal epoxide hydrolase gene (EPHX1), T113C and A139G, may influence susceptibility to chronic obstructive pulmonary disease (COPD) and asthma. We genotyped participants from the Copenhagen City Heart Study (n = 10,038) and the Copenhagen General Population Study (n = 37,022) for the T113C and A139G variants in the EPHX1 gene and measured lung function and recorded COPD hospitalisation and asthma and smoking history. Finally, we meta-analysed results from 19 studies including 7,489 COPD cases and 42,970 controls. The OR for spirometry-defined COPD or COPD hospitalisation did not differ from 1.0 for any of the EPHX1 genotypes or phenotypes overall, or in smokers or nonsmokers separately (p-value for trend 0.18-0.91). Likewise, EPHX1 genotypes or phenotypes did not associate with risk of asthma (p-value for trend 0.46-0.98). In meta-analysis, random effects OR for COPD in T113C heterozygotes and homozygotes versus non-carriers were 1.17 (0.99-1.38) and 1.38 (1.09-1.74), respectively. Corresponding values for A139G were 0.93 (0.83-1.05) and 0.89 (0.78-1.02). Our results indicate that genetically reduced microsomal epoxide hydrolase activity is not a major risk factor for COPD or asthma in the Danish population; however, meta-analysis cannot completely exclude a minor effect on COPD risk.
Assuntos
Epóxido Hidrolases/genética , Doença Pulmonar Obstrutiva Crônica/genética , Asma/genética , Estudos de Casos e Controles , Estudos Transversais , Dinamarca , Volume Expiratório Forçado , Variação Genética , Genótipo , Heterozigoto , Homozigoto , Humanos , Pulmão/metabolismo , Fatores de Risco , Fumar/efeitos adversos , Espirometria/métodosRESUMO
OBJECTIVES: The scavenger receptor A-I/II (SRA-I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA-I/II gene, Arg293X, truncates the distal collagen-like domain, which is essential for ligand recognition. We tested whether the Arg293X variant is associated with reduced lung function and risk of chronic obstructive pulmonary disease (COPD) in the general population. METHODS: We genotyped 48,741 individuals from the adult Danish general population for Arg293X, and recorded lung function and spirometry-defined COPD. RESULTS: Arg293X homozygotes (n = 5) and heterozygotes (n = 587), compared with noncarriers (n = 48,149), had a 6% and 1% reduction in predicted percentage of forced vital capacity (FVC % predicted) (P = 0.05) and a nonsignificant 7% and 1% reduction in predicted percentage of forced expiratory volume in one second (FEV(1) % predicted) (P = 0.06), respectively. The Arg293X genotype interacted with gender (P = 0.004) and α(1) -antitrypsin MZ heterozygosity (P = 0.049), but not with superoxide dismutase-3 E1I1 heterozygosity (P = 0.11) in determining FEV(1) % predicted. Amongst men, FEV(1) % predicted and FVC % predicted were both reduced by 4% (P = 0.0004 and P = 0.0003, respectively) in Arg293X heterozygotes compared with noncarriers. Corresponding values were 14% (P = 0.03) and 11% (P = 0.04) amongst MZ heterozygotes, and 9% (P = 0.03) and 8% (P = 0.04) amongst E1I1 heterozygotes, compared with noncarriers. Lung function did not differ between Arg293X heterozygotes and noncarriers amongst females or individuals without MZ and E1I1. Arg293X heterozygosity was associated with spirometry-defined COPD amongst men [odds ratio (95% confidence interval): 1.7 (1.1-2.4)], but not with COPD in the whole cohort or in any other subgroup. CONCLUSIONS: SRAI/II Arg293X heterozygotes have reduced lung function and increased COPD risk amongst men. They also have reduced lung function amongst individuals heterozygous for the α(1)-antitrypsin MZ and superoxide dismutase-3 E1I1 genotypes.
Assuntos
Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Receptores Depuradores Classe A/genética , Adulto , Idoso , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Volume Expiratório Forçado/genética , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores Sexuais , Capacidade Vital/genéticaRESUMO
AIM: To develop a rapid method for diagnosing lung maturity at birth with the purpose of administering surfactant early to infants with immature lungs and to spare infants with mature lungs from this treatment. METHODS: Lamellar body counts (LBC) on gastric aspirates from 191 newborns were counted in the platelet window in automatic blood cell counters. A preliminary study was performed on 108 aspirates from 2000 in infants with <32 weeks' gestation. Furthermore, 83 aspirates from 2004 to 2005 in infants with <30 weeks' gestation were analysed. RESULTS: Lamellar bodies in gastric aspirate were identified by electron microscopy. Seventy of the aspirates from 2004 to 2005 were analysed with a Sysmex XE-2100 (Sysmex, Holbaek, Naestved, Odense and Rigshospitalet, Denmark) counter. Twenty-four of these infants developed moderate to severe respiratory distress syndrome (RDS). The best cut-off value was 8000/µL with a sensitivity of 75% and a specificity of 72%. Forty-four of the 70 aspirates from 2004 to 2005 were analysed by Sysmex, Advia 120 and Cell-Dyn 4000. Thirteen other aspirates from 2004 to 05 were analysed by Sysmex and Coulter Counter LH755. Using Advia and Coulter the results were similar to Sysmex, but LBC obtained with Cell-Dyn were not correlated with the development of RDS. CONCLUSION: Lamellar body counts on gastric aspirate is a promising tool for prediction of development of RDS in infants of <30 weeks` gestation.
Assuntos
Organelas , Síndrome do Desconforto Respiratório do Recém-Nascido/patologia , Líquidos Corporais/citologia , Contagem de Células , Humanos , Recém-Nascido , Microscopia Eletrônica , Organelas/ultraestrutura , Valor Preditivo dos Testes , EstômagoRESUMO
Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.
Assuntos
Farmacogenética , Psiquiatria , Antidepressivos/farmacologia , Monitoramento de Medicamentos , Humanos , NeuroimagemRESUMO
OBJECTIVES: The United States Food & Drug Administration released an advisory in 2016 that fluoroquinolones be relegated to second-line agents for uncomplicated urinary tract infections (UTIs) given reports of rare but serious side effects; similar warnings have followed from Health Canada and the European Medicines Agency. The objective was to determine whether alternative non-fluoroquinolone agents are as effective as fluoroquinolones in the treatment of UTIs. METHODS: We conducted a retrospective population-based cohort study using administrative health data from six Canadian provinces. We identified women (n = 1 585 997) receiving antibiotic treatment for episodes of uncomplicated UTIs (n = 2 857 243) between January 1 2005 and December 31 2015. Clinical outcomes within 30 days from the initial antibiotic dispensation were compared among patients treated with a fluoroquinolone versus non-fluoroquinolone agents. High-dimensional propensity score adjustments were used to ensure comparable treatment groups and to minimize residual confounding. RESULTS: Fluoroquinolone use for UTI declined over the study period in five of six Canadian provinces and accounted for 22.3-48.5% of treatments overall. The pooled effect across the provinces indicated that fluoroquinolones were associated with fewer return outpatient visits (OR 0.89, 95%CI 0.87-0.92), emergency department visits (OR 0.74, 95%CI 0.61-0.89), hospitalizations (OR 0.83, 95%CI 0.77-0.88), and repeat antibiotic dispensations (OR 0.77, 95%CI 0.75-0.80) within 30 days. CONCLUSIONS: Fluoroquinolones are associated with improved clinical outcomes among women with uncomplicated UTIs. This benefit must be weighed against the risk of fluoroquinolone resistance and rare but serious fluoroquinolone side effects when selecting first-line treatment for these patients.