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1.
Acta Psychiatr Scand ; 139(1): 68-77, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30182363

RESUMO

OBJECTIVE: To investigate whether continued use of non-aspirin NSAID, low-dose aspirin, high-dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population-based registers. METHODS: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in-patient or out-patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants. RESULTS: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low-dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident depression. CONCLUSION: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population-based registers to systematically identify drugs with repurposing potential.


Assuntos
Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Estresse Fisiológico/efeitos dos fármacos , Adulto , Idoso , Alopurinol/efeitos adversos , Alopurinol/uso terapêutico , Angiotensinas/efeitos adversos , Angiotensinas/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antidepressivos/uso terapêutico , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Dinamarca/epidemiologia , Depressão/diagnóstico , Depressão/epidemiologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/epidemiologia , Reposicionamento de Medicamentos/estatística & dados numéricos , Feminino , Supressores da Gota/efeitos adversos , Supressores da Gota/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Incidência , Inflamação/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Sistema de Registros
2.
Acta Psychiatr Scand ; 139(3): 227-236, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30383306

RESUMO

OBJECTIVE: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available laboratory tests. We aimed to combine data from different molecular levels and tissues into a composite diagnostic and state biomarker. METHODS: Expression levels of 19 candidate genes in peripheral blood, plasma levels of BDNF, NT-3, IL-6 and IL-18, leukocyte counts, and urinary markers of oxidative damage to DNA and RNA were measured in 37 adult rapid-cycling patients with BD in different affective states during a 6- to 12-month period and in 40 age- and gender-matched healthy individuals in a longitudinal, repeated measures design comprising a total of 211 samples. A composite biomarker was constructed using data-driven variable selection. RESULTS: The composite biomarker discriminated between patients with BD and healthy control individuals with an area under the receiver operating characteristic curve (AUC) of 0.83 and a sensitivity of 73% and specificity of 71% corresponding with a moderately accurate test. Discrimination between manic and depressive states had a moderate accuracy, with an AUC of 0.82 and a sensitivity of 92% and a specificity of 40%. CONCLUSION: Combining individual biomarkers across tissues and molecular systems could be a promising avenue for research in biomarker models in BD.


Assuntos
Transtorno Bipolar/sangue , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/urina , Expressão Gênica , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Técnicas e Procedimentos Diagnósticos/normas , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto Jovem
3.
Acta Psychiatr Scand ; 139(1): 26-36, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30374965

RESUMO

OBJECTIVE: Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period. METHOD: One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels. RESULTS: From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide. CONCLUSION: The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.


Assuntos
Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Estado Pré-Diabético/tratamento farmacológico , Adolescente , Adulto , Idoso , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Peptídeo C/efeitos dos fármacos , Clozapina/efeitos adversos , Clozapina/uso terapêutico , Dinamarca/epidemiologia , Jejum , Feminino , Seguimentos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Liraglutida/administração & dosagem , Liraglutida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade/induzido quimicamente , Obesidade/epidemiologia , Olanzapina/efeitos adversos , Olanzapina/uso terapêutico , Sobrepeso/induzido quimicamente , Sobrepeso/epidemiologia , Placebos/administração & dosagem , Estado Pré-Diabético/induzido quimicamente , Estado Pré-Diabético/epidemiologia , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Adulto Jovem
4.
Diabetologia ; 55(5): 1338-45, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22349073

RESUMO

AIMS/HYPOTHESIS: Heritability estimates have shown a varying degree of genetic contribution to traits related to type 2 diabetes. Therefore, the objective of this study was to investigate the familiality of fasting and stimulated measures of plasma glucose, serum insulin, serum C-peptide, plasma glucose-dependent insulinotropic polypeptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) among non-diabetic relatives of Danish type 2 diabetic patients. METHODS: Sixty-one families comprising 193 non-diabetic offspring, 29 non-diabetic spouses, 72 non-diabetic relatives (parent, sibling, etc.) and two non-related relatives underwent a 4 h 75 g OGTT with measurements of plasma glucose, serum insulin, serum C-peptide, plasma GIP and plasma GLP-1 levels at 18 time points. Insulin secretion rates (ISR) and beta cell responses to glucose, GIP and GLP-1 were calculated. Familiality was estimated based on OGTT-derived measures. RESULTS: A high level of familiality was observed during the OGTT for plasma levels of GIP and GLP-1, with peak familiality values of 74 ± 16% and 65 ± 15%, respectively (h (2) ± SE). Familiality values were lower for plasma glucose, serum insulin and serum C-peptide during the OGTT (range 8-48%, 14-44% and 15-61%, respectively). ISR presented the highest familiality value at fasting reaching 59 ± 16%. Beta cell responsiveness to glucose, GLP-1 and GIP also revealed a strong genetic influence, with peak familiality estimates of 62 ± 13%, 76 ± 15% and 70 ± 14%, respectively. CONCLUSIONS/INTERPRETATION: Our results suggest that circulating levels of GIP and GLP-1 as well as beta cell response to these incretins are highly familial compared with more commonly investigated measures of glucose homeostasis such as fasting and stimulated plasma glucose, serum insulin and serum C-peptide.


Assuntos
Jejum , Polipeptídeo Inibidor Gástrico/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Peptídeo C/sangue , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade
5.
J Dairy Sci ; 95(11): 6457-64, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22939796

RESUMO

Digital dermatitis (DD) refers to painful lesions primarily affecting the skin in the interdigital region of dairy cattle. The purpose of this study was to evaluate the dynamics of DD in 39 cows, observed at approximately 3-d intervals, for the first 6 mo of lactation. Specifically, the study aimed at evaluating different levels of DD susceptibility in cows, identifying the bacterial colonization of the interdigital skin, and exploring the relationship between clinical DD diagnosis and laboratory findings. Three different susceptibility categories were identified for DD: 1=consistently healthy cow; 2=intermittently infected cow; and 3=consistently infected cow. Susceptibility categories were associated with age at calving. The average age at calving was 775 d (SD ±43.4), with the youngest heifer calving at age 669 d and the oldest heifer at 858 d. Advancing age at calving was associated with greater odds of being intermittently or consistently infected. This corresponded with an odds ratio of 2.02 over a period of 30 d. During the study period, 161 DD lesions were identified in 28 of the 39 cows (72%). Of those 28 cows, 13 cows were consistently infected. The remaining 11 of the 39 cows (28%) showed slight thickening of the skin with no pain (5 cows) and no signs of skin changes (6 cows). Histopathology and fluorescence in situ hybridization were possible to perform on 132 biopsy samples. A clinical diagnosis of DD was confirmed in 70% of the lesions by histopathology, and colonization of Treponema spp. Dichelobacter nodosus was found in 35 samples (29%).


Assuntos
Doenças dos Bovinos/transmissão , Dermatite Digital/transmissão , Fatores Etários , Animais , Biópsia/veterinária , Bovinos , Doenças dos Bovinos/diagnóstico , Doenças dos Bovinos/microbiologia , Doenças dos Bovinos/patologia , Dichelobacter nodosus , Dermatite Digital/diagnóstico , Dermatite Digital/microbiologia , Dermatite Digital/patologia , Suscetibilidade a Doenças/veterinária , Feminino , Infecções por Bactérias Gram-Negativas/veterinária , Hibridização in Situ Fluorescente/veterinária , Lactação , Gravidez , Pele/patologia , Treponema , Infecções por Treponema/veterinária
6.
Phys Rev Lett ; 106(24): 242302, 2011 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-21770567

RESUMO

We report on an exclusive and kinematically complete high-statistics measurement of the basic double-pionic fusion reaction pn→dπ(0)π(0) over the full energy region of the ABC effect, a pronounced low-mass enhancement in the ππ-invariant mass spectrum. The measurements, which cover also the transition region to the conventional t-channel ΔΔ process, were performed with the upgraded WASA detector setup at COSY. The data reveal the Abashian-Booth-Crowe effect to be uniquely correlated with a Lorentzian energy dependence in the integral cross section. The observables are consistent with a narrow resonance with m=2.37 GeV, Γ≈70 MeV and I(J(P))=0(3(+)) in both pn and ΔΔ systems. Necessary further tests of the resonance interpretation are discussed.

7.
Eur J Clin Microbiol Infect Dis ; 29(10): 1195-201, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20706855

RESUMO

The prevalence of antibiotic resistance and their genetic determinants in colonizing group B streptococci (GBS) sampled in a Swedish nationwide survey was examined. In five GBS isolates (1.3%), kanamycin/amikacin resistance and the presence of the aphA-3 gene was identified. Three of these isolates carried the aad-6 gene and were streptomycin-resistant. Screening with kanamycin and streptomycin 1,000-µg disks enabled a rapid and easy detection of these isolates. In all, 312/396 (79%) GBS were tetracycline-resistant and 95% of the examined isolates harbored the tetM gene. Among the 22 (5.5%) GBS resistant to erythromycin and/or clindamycin, the ermB gene was detected in nine isolates (41%) and erm(A/TR) in ten isolates (45%). A high level of erythromycin and clindamycin resistance with minimum inhibitory concentrations (MICs) >256 mg/L was found in four serotype V isolates that harbored ermB. The erythromycin/clindamycin resistance was distributed among all of the common serotypes Ia, Ib, II, III, IV, and V, but was not present in any of the 44 serotype III isolates associated to clonal complex 17. Screening for penicillin resistance with 1-µg oxacillin disks showed a homogenous population with a mean inhibition zone of 20 mm. A change in the present oxacillin breakpoints for GBS is suggested.


Assuntos
Antibacterianos/farmacologia , Portador Sadio/microbiologia , Farmacorresistência Bacteriana , Complicações Infecciosas na Gravidez/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus agalactiae/efeitos dos fármacos , Técnicas de Tipagem Bacteriana , DNA Bacteriano/genética , Feminino , Genes Bacterianos , Humanos , Recém-Nascido , Testes de Sensibilidade Microbiana/métodos , Gravidez , Reto/microbiologia , Sorotipagem , Pele/microbiologia , Streptococcus agalactiae/isolamento & purificação , Suécia , Vagina/microbiologia
8.
J Dairy Sci ; 92(2): 607-16, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19164671

RESUMO

The aim was to describe the clinical orthopedic implications of oligofructose overload. A group of 8 nonpregnant dairy heifers were given an oral dose of oligofructose (17 g/kg of body weight). At predefined times during a period spanning 3 d before and 9 d after oligofructose overload, the heifers underwent a clinical examination including locomotion scoring, hoof-testing, and palpation of tarso-crural joints, as well as the collection of blood and ruminal fluid samples. Locomotion sessions were videotaped; subsequently, locomotion was blind-scored. Locomotion scores increased after oligofructose overload and declined toward the end of the study period. The greatest locomotion scores were recorded on d 3 to 5 (60 to 120 h) where 12 of 42 (29%) locomotion scores were 3 and 13 of 42 (32%) were score 2. Positive reactions to hoof-testing were observed from 30 h after oligofructose overload and reached a maximum on d 7 and 9 where 12 of 28 (43%) reactions were marked positive. Distension of the tarso-crural joints was observed from 24 h after oligofructose overload, with maximum distension being observed on d 2, in which 44 of 56 (79%) of observed joints were either moderately or severely distended. The heifers developed classic signs of acute ruminal and systemic acidosis after the oligofructose overload (ruminal pH 4.3 +/- 0.07, standard base excess -10.8 +/- 2.3 at 18 h). With few exceptions, clinical and laboratory variables returned to normal within 9 d of oligofructose overload. But, good body condition and previous feeding with grass apparently predisposed the heifers to more severe systemic affection. Oligofructose overload in dairy heifers induced ruminal and systemic acidosis, diarrhea, dehydration, and, subsequently, lameness, claw pain, and joint effusion, collectively interpreted as signs of acute laminitis. Oligofructose overload at 17 g/kg of body weight represented a relatively mild laminitis model in cattle, as demonstrated by a reasonably quick recovery from systemic as well as orthopedic signs.


Assuntos
Doenças dos Bovinos/induzido quimicamente , Coxeadura Animal/induzido quimicamente , Locomoção/efeitos dos fármacos , Oligossacarídeos/farmacologia , Animais , Bovinos , Feminino , Conteúdo Gastrointestinal/química , Conteúdo Gastrointestinal/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hematócrito/veterinária , Casco e Garras/patologia , Articulações/patologia , Locomoção/fisiologia , Gravidez , Rúmen/efeitos dos fármacos , Rúmen/metabolismo , Fatores de Tempo , Gravação em Vídeo
9.
Radiat Prot Dosimetry ; 126(1-4): 18-22, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17510200

RESUMO

A new quasi-monoenergetic neutron beam facility has been constructed at The Svedberg Laboratory (TSL) in Uppsala, Sweden. Key features include a neutron energy range of 11-175 MeV, high fluxes, user flux control, flexible neutron field size and shape, and spacious and easily accessible user area. The first results of the beam characterisation measurements are reported.


Assuntos
Nêutrons , Aceleradores de Partículas/instrumentação , Radiometria/instrumentação , Desenho de Equipamento , Análise de Falha de Equipamento , Doses de Radiação , Suécia
10.
Cancer Res ; 57(10): 2048-54, 1997 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-9158004

RESUMO

Previous investigations have supported or indicated a stimulatory role of the insulin-like growth factor II gene (IGF2) in hepatocarcinogenesis. We have studied the transcript levels, promoter usage, and imprinting status of the ICF2 gene and its relationship to H19 in human hepatocellular carcinomas (HCCs) and liver tumor cell lines. The activity of the IGF2 promoter P1 was lost in about 70% of the cases (18 of 25). This is the most prominent abnormality regarding the IGF2 regulation in this study. Total IGF2 as well as promoter P3 transcription were up-regulated in a small group of the tumors. Twenty genetically informative cases were obtained from 26 cases, thus excluding the probability of loss of heterozygosity of the IGF2 gene. Among these, nine showed abnormal monoallelic expression of IGF2. One HCC and one HCC cell line proved loss of functional imprinting of IGF2. H19 and IGF2 were regulated in parallel, and expression levels were variable. Taken together, the disruption of the IGF2 promoter regulation, particularly the loss of P1 activity, is a common feature of human HCCs. The loss of P1 activity explains the frequent loss of biallelic IGF2 expression and may potentially be used as a diagnostic or monitoring marker for human HCC.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento Insulin-Like II/genética , Neoplasias Hepáticas/genética , Regiões Promotoras Genéticas , RNA não Traduzido , Alelos , Carcinoma Hepatocelular/metabolismo , Éxons , Deleção de Genes , Expressão Gênica , Heterozigoto , Humanos , Fator de Crescimento Insulin-Like II/biossíntese , Neoplasias Hepáticas/metabolismo , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , RNA Longo não Codificante , RNA Mensageiro/metabolismo
11.
Diabetes ; 49(9): 1608-11, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10969849

RESUMO

The human plasma-cell membrane differentiation antigen-1 (PC-1) has been shown to inhibit insulin receptor tyrosine kinase activity. Recently, a K121Q polymorphism in the human PC-1 gene was found in a Sicilian population and was shown to be strongly associated with insulin resistance. The objectives of the present investigation were to examine in the Danish Caucasian population whether the K121Q variant was associated with type 2 diabetes or, in glucose-tolerant subjects, with impaired whole-body insulin sensitivity. We genotyped 404 Danish type 2 diabetic patients and found that the allele frequency of the variant was 0.14 (95% CI 0.12-0.16), whereas the allele frequency was 0.16 (95% CI 0.13-0.19) among 237 matched glucose-tolerant control subjects (P = 0.6). In the control subjects, there were no significant differences among wild-type, heterozygous, or homozygous subjects in regard to 1) serum insulin and plasma glucose levels at fasting, 60 min, or 120 min during an oral glucose tolerance test (OGTT) or 2) the estimates of insulin resistance obtained from the homeostasis model assessment (HOMA). Furthermore, we investigated the impact of the variant in 2 other Danish population samples that comprised 356 young healthy subjects and 226 glucose-tolerant offspring of type 2 diabetic probands, respectively. In all of the study populations, the polymorphism was not associated with an altered insulin sensitivity index as estimated from an intravenous glucose tolerance test in combination with an intravenous injection of tolbutamide. In addition, among the 226 offspring, the variations in serum insulin and serum C-peptide responses measured during an OGTT were not related to the PC-1 genotype. In conclusion, the K121Q polymorphism of the human PC-1 gene is not associated with type 2 diabetes or insulin resistance among Danish Caucasians.


Assuntos
Diabetes Mellitus Tipo 2/genética , Variação Genética , Resistência à Insulina/genética , Glicoproteínas de Membrana/genética , Diester Fosfórico Hidrolases , Pirofosfatases , População Branca/genética , Adulto , Idoso , Substituição de Aminoácidos , Glicemia/metabolismo , Dinamarca , Feminino , Heterozigoto , Homozigoto , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade
12.
J Clin Endocrinol Metab ; 83(12): 4506-9, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9851800

RESUMO

The third form of maturity-onset diabetes of the young is caused by mutations in the hepatocyte nuclear factor-1alpha gene. Recently, we demonstrated an association between a prevalent polymorphism at codon 98, Ala/Val98, of this gene and a 20% decreased insulin release during an oral glucose tolerance test (OGTT) in middle-aged glucose-tolerant Danish Caucasian subjects. The major objective of the present study was to replicate this finding among glucose-tolerant first degree relatives of type 2 diabetic patients of the same ethnic origin. All participants, 231 glucose-tolerant offspring of 62 type 2 diabetic probands, underwent an OGTT with measurements of plasma glucose, serum insulin, and serum C peptide during the test. Thirty-three heterozygous carriers of the Ala/Val variant were identified, whereas no subjects had the variant in its homozygous form. Ala/Val carriers had a 20% reduction in serum C peptide at 30 min during the OGTT (1225+/-636 vs. 1507+/-624 pmol/L; P=0.02) compared to wild-type carriers. No significant differences in serum insulin levels during the OGTT were observed between carriers of the variant and Ala/Ala homozygotes. In conclusion, among Danish glucose-tolerant first degree relatives of type 2 diabetic patients the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene is associated with a decreased serum C-peptide secretion during an OGTT. This finding confirms our previously reported observation of the functional importance of the variant to insulin secretion during an OGTT among middle-aged healthy subjects.


Assuntos
Peptídeo C/sangue , Proteínas de Ligação a DNA , Diabetes Mellitus/genética , Variação Genética/genética , Teste de Tolerância a Glucose , Proteínas Nucleares , Polimorfismo Genético/genética , Fatores de Transcrição/genética , Adulto , Sequência de Aminoácidos/genética , Diabetes Mellitus/fisiopatologia , Feminino , Glucose/fisiologia , Fator 1 Nuclear de Hepatócito , Fator 1-alfa Nuclear de Hepatócito , Fator 1-beta Nuclear de Hepatócito , Humanos , Masculino , Pessoa de Meia-Idade
13.
J Clin Endocrinol Metab ; 83(11): 3992-5, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9814481

RESUMO

The objective of the present study was to investigate whether the frequent amino acid polymorphisms, Ile/Leu27 and Ser/Asn487, of the hepatocyte nuclear factor-1alpha gene were associated with alterations in glucose-induced serum C-peptide and serum insulin responses among glucose-tolerant first-degree relatives of type 2 diabetic patients. The study comprised 2 independent Danish cohorts. Among 74 unrelated type 2 diabetic relatives, 12 homozygous carriers of the Ile/Leu27 polymorphism had a 32% decrease in the 30-min serum C-peptide level (P = 0.01), as well as a 39% decrease in the 30-min serum insulin level (P = 0.02) during an oral glucose tolerance test. Ten homozygous carriers of the Ile/Leu27 variant did, however, not differ from wild-type carriers, with respect to the acute circulating insulin and serum C-peptide responses during an i.v. glucose tolerance test in the same study cohort. In a larger (more than 3-fold) study group of 230 glucose tolerant offspring of 62 type 2 diabetic probands, 33 homozygous carriers of the Ile/Leu27 variant did not differ, with respect to either serum insulin and serum C-peptide levels during an oral glucose tolerance test or acute serum insulin and serum C-peptide responses during an i.v. glucose tolerance test. We therefore consider the former positive finding as a statistical type I error. There were no differences in the above mentioned variables between carriers of the Ser/Asn487 polymorphism and wild-type carriers within any of the 2 study populations. Nor did carriers of combined genotypes, i.e. carriers of both the Ile/Leu27 and the Ser/Asn487 variants, show any associations with the examined variables. In conclusion, the Ile/Leu27 and Ser/ Asn487 polymorphisms of the hepatocyte nuclear factor-1alpha gene have apparently no major impact on the pancreatic beta-cell function, after an oral and i.v. glucose challenge, in Caucasian first-degree relatives of type 2 diabetic patients.


Assuntos
Proteínas de Ligação a DNA , Diabetes Mellitus Tipo 2/genética , Variação Genética , Ilhotas Pancreáticas/fisiologia , Proteínas Nucleares/genética , Fatores de Transcrição/genética , População Branca/genética , Adulto , Substituição de Aminoácidos , Asparagina , Peptídeo C/metabolismo , Feminino , Teste de Tolerância a Glucose , Fator 1 Nuclear de Hepatócito , Fator 1-alfa Nuclear de Hepatócito , Fator 1-beta Nuclear de Hepatócito , Humanos , Insulina/sangue , Isoleucina , Leucina , Masculino , Pessoa de Meia-Idade , Serina
14.
J Clin Endocrinol Metab ; 84(2): 553-60, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10022415

RESUMO

We investigated the acute (4-5 h) and short-term (5 days) effects of GH treatment on hepatic messenger RNA (mRNA) levels of the genes for the insulin-like growth factors (IGFs), insulin-like growth factor binding protein-1, -2, and -3 (IGFBPs), and the acid labile subunit (ALS), as well as serum levels of these proteins in humans. At the mRNA level, we observed an increase in IGF-1 transcription (+173%) following GH treatment in the acute group, which remained elevated in the short-term treatment group. IGFBP-2 mRNA decreased after short-term GH treatment, without changes in IGFBP-1 or -3 expression. The ALS transcript level increased after 5 days. In serum, we found increased levels of IGF-I and insulin, and decreased levels of IGF-II, in the short-term treatment group. IGFBP-1 decreased in both treatment groups, whereas IGFBP-2 was reduced after 5 days treatment. ALS increased in the short-term group. We observed increased IGFBP-3 serum levels after 5 days of GH treatment, likely due to increased formation of the ternary complex. Our results show that the metabolic effects by GH on the IGF axis are complex. In addition to a direct stimulation of IGF-I and ALS expression, GH inhibits IGFBP-1 serum levels and IGFBP-2 expression in an indirect manner, possibly facilitating enhanced IGF bioavailability to target tissues.


Assuntos
Hormônio do Crescimento Humano/farmacologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , RNA Mensageiro/metabolismo , Adulto , Proteínas de Transporte/sangue , Proteínas de Transporte/genética , Feminino , Glicoproteínas/sangue , Glicoproteínas/genética , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/genética , Masculino , Pessoa de Meia-Idade
15.
J Clin Endocrinol Metab ; 85(4): 1606-10, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10770205

RESUMO

Insulin-like growth factor I (IGF-I) is an important regulator of many aspects of growth, differentiation, and development, and as low birth weight has been associated with impaired glucose tolerance and overt type 2 diabetes in adult life, we considered the genes encoding the IGF-I and the IGF-I receptor (IGF-IR) as candidates for low birth weight, insulin resistance, and type 2 diabetes. Here we report the mutational analysis of the coding regions of the IGF-I and IGF-IR performed on genomic DNA from probands of 82 Danish type 2 diabetic families. No mutations predicting changes in the amino acid sequences of the IGF-I or IGF-IR genes were detected, but several silent and intronic polymorphisms were found. The impact of the most prevalent polymorphism, GAG1013GAA of the IGF-IR, was evaluated in a population-based sample of 349 young healthy subjects, where the variant had an allele frequency of 0.44 (95% confidence interval, 0.40-0.48). No significant relationships between this variant and birth weight, birth length, or insulin sensitivity index were detected. In addition, we did not observe any significant differences in allelic frequencies of the codon 1013 variant between 395 type 2 diabetic patients (allele frequency, 0.52; 95% confidence interval, 0.49-0.55) and 238 matched glucose-tolerant control subjects (allelic frequency, 0.47; 95% confidence interval, 0.43-0.50). In conclusion, variability in the coding regions of IGF-I and the IGF-IR does not associate with reduced birth weight, insulin sensitivity index, or type 2 diabetes in the Danish population.


Assuntos
Diabetes Mellitus Tipo 2/genética , Fator de Crescimento Insulin-Like I/genética , Mutação , Receptor IGF Tipo 1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Peso ao Nascer , Códon , Análise Mutacional de DNA , Dinamarca , Feminino , Frequência do Gene , Humanos , Insulina/sangue , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
16.
J Endocrinol ; 172(3): 457-65, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11874694

RESUMO

The regulation of the insulin-like growth factor-II gene (IGF2) is complex and involves the usage of four promoters resulting in different 5' untranslated regions, but with a common translated product. The IGF2 gene product is a mitogenic and survival factor that has been suggested to be important for a normal fetal development and cancer. In this paper we present evidence suggesting that the human IGF2 gene is regulated by GH, and that this regulation occurs in a promoter-specific way. Three lines of evidence support this finding. First, in vivo data from patients treated with GH (one injection or daily injections for 5 consecutive days) showed an increase in the IGF2 P2 promoter derived transcript after acute treatment, and of the P4 promoter transcript after short-term treatment while the P1 promoter derived transcript did not show any significant change. Secondly, isolated human liver cells treated with GH for 2 h displayed an upregulation of the P2 promoter derived transcript. Thirdly, employing transfection experiments in GH-receptor positive CHO cells with P2 and P4 promoter-luciferase constructs, an upregulation by GH was evident, while a P1 promoter construct was unresponsive. We suggest that GH may be a physiological regulator of IGF2 in humans.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Fator de Crescimento Insulin-Like II/genética , Regiões Promotoras Genéticas , Transcrição Gênica , Análise de Variância , Animais , Células CHO , Células Cultivadas , Cricetinae , Humanos , Fator de Crescimento Insulin-Like II/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo
17.
Int J Mol Med ; 6(2): 161-9, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10891560

RESUMO

Hepatoblastoma is a rare pediatric liver tumor. While much progress has been made in the treatment of the disease, very little is known about the moleculer events underlying the pathogenesis of this disease. We sought to investigate a series of hepatoblastomas for alterations in gene expression patterns with emphasis on important cell regulatory genes, including chromatin modifying enzymes, cyclin dependent kinase inhibitors, growth factors, oncogenes and cell cycle regulators. Total RNA was extracted from a series of sporadic hepatoblastomas with matched normal liver, some unmatched tumors and fetal livers, and gene expression was measured for various genes using RNase Protection Analysis (RPA). The results of this analysis show that the expression of many important regulatory genes are distinctly altered in these tumors, and a subset of tumors can be distinguished on the basis of these gene expression differences and histopathological features. Because the molecular events underlying the pathogenesis of this rare tumor are so poorly understood, this study represents a first step in determining some of the possible mechanisms involved which may provide future avenues of research.


Assuntos
Regulação Neoplásica da Expressão Gênica , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Pré-Escolar , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/metabolismo , Feminino , Perfilação da Expressão Gênica , Genes do Retinoblastoma/fisiologia , Genes p53/fisiologia , Hepatoblastoma/patologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Lactente , Fígado/embriologia , Fígado/fisiologia , Neoplasias Hepáticas/patologia , Masculino , Proto-Oncogenes/genética , Proto-Oncogenes/fisiologia , Sondas RNA , Valores de Referência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-18238659

RESUMO

Estimation of an atomic clock's frequency stability, separate from its reference, is often done using a three-cornered hat procedure. A major requirement for the success of this method is that clocks be uncorrelated. If this requirement is not satisfied, the three-cornered hat procedure can lead to misleading or even negative variance estimates. Others have considered this problem and developed an analysis that allows for the possibility of cross correlation between clocks. We have extended and applied these ideas to obtain mathematically consistent frequency stability estimates on atomic clock data from the U.S. Naval Observatory. In addition, we derived an expression for the clock weights that produce a minimum variance combination of clocks in the presence of correlations.

19.
Equine Vet J ; 45(5): 564-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23294287

RESUMO

REASONS FOR PERFORMING STUDY: Incisional infections are common in horses after colic surgery. There is a clinical impression that the use of a stent bandage reduces the prevalence of such infections. OBJECTIVE: To determine the effect of a stent bandage on the likelihood of incisional infection after ventral midline exploratory coeliotomy. It was hypothesised that the use of a stent bandage would reduce the likelihood of incisional infection. METHODS: Medical records of horses that underwent exploratory coeliotomy for colic between January 2005 and September 2011 were reviewed. Inclusion criteria were animals that had one ventral midline coeliotomy and had survived at least 10 days after surgery. Horses were categorised into 2 groups:no-stent group and stent group. The following data were collected for each case: age, sex, weight, heart rate, packed cell volume, primary lesion, performance of an enterotomy or intestinal resection, surgical classification, use of local antimicrobials, duration of surgery, intra-abdominal administration of sodium carboxymethylcellulose, intravenous administration of lidocaine, surgeon, use of a stent bandage, duration of stent use, and use of a belly band. Factors associated with the outcome measure 'wound infection' vs. 'no wound infection' were analysed using a generalised linear mixed model for logistic regression with surgeon as a random effect. RESULTS: The inclusion criteria were met in 130 horses: 55 were assigned to the no-stent group and 75 to the stent group. In the no-stent group, 12 (21.8%) horses developed incisional infections, whereas only 2 horses (2.7%) in the stent group had incisional infections. In the stent group, no incisional infections were observed during the last 20 months of the study. Statistical analysis showed that only the effect of the use of a stent bandage was significant (P = 0.005). CONCLUSIONS: The prevalence of incisional infections when a stent bandage was used was 2.7%, a finding that compared favourably to information in the literature. Use of a stent bandage significantly reduced the likelihood of incisional infections. POTENTIAL RELEVANCE: A stent bandage would reduce the likelihood of incisional infection in horses undergoing exploratory coeliotomy for colic.


Assuntos
Cólica/veterinária , Bandagens Compressivas/veterinária , Doenças dos Cavalos/cirurgia , Laparotomia/veterinária , Infecção da Ferida Cirúrgica/veterinária , Animais , Cólica/cirurgia , Feminino , Cavalos , Laparotomia/efeitos adversos , Masculino , Infecção da Ferida Cirúrgica/prevenção & controle , Resultado do Tratamento
20.
Equine Vet J Suppl ; (39): 63-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21790756

RESUMO

REASONS FOR PERFORMING STUDY: Previous studies indicate similar overall survival of horses with nephrosplenic entrapment of the large colon (NSE), regardless of treatment strategy. Short-term survival of a primarily conservative treatment strategy without rolling under general anaesthesia (GA) and a low proportion of surgical intervention as well as indicators of short-term nonsurvival has not been documented. OBJECTIVES: To document short-term survival of horses with NSE treated in a university referral hospital with a low rate of surgical interventions and to determine factors associated with the decision of treatment and short-term nonsurvival. METHODS: A retrospective review of medical records of 142 horses diagnosed with NSE between January 2000 and October 2009 was undertaken. Case details and clinical parameters from the initial examination, treatment and outcome were recorded. Factors associated with decision of treatment and short-term survival were identified by multiple logistic regression analysis. RESULTS: Warmblood breeds were over-represented in comparison to the general colic population. Overall short-term survival was 91.5% (130/142) which is similar to previous studies. Three horses considered to be in need of surgery were subjected to euthanasia for economical reasons before treatment. Of 114 conservatively treated horses, 110 (96.5%) survived, as did 20/25 (80%) of surgically treated horses. Nine conservatively managed horses were treated with phenylephrine. Gastric reflux (P = 0.0077), pain (P = 0.024) and abdominal distension (P = 0.05) were associated with the decision to treat surgically. Increased heart rate (P<0.001), and surgery (P = 0.032) were associated with reduced likelihood of short-term survival. CONCLUSIONS AND POTENTIAL RELEVANCE: Overall short-term survival was similar to that reported in previous studies with higher proportions of surgically managed cases. Consequently, horses with NSE should be managed by a primarily conservative treatment strategy, with the decision to treat surgically based on specific evidence based criteria.


Assuntos
Cólica/terapia , Doenças do Colo/terapia , Doenças dos Cavalos/terapia , Animais , Cólica/mortalidade , Cólica/patologia , Doenças do Colo/mortalidade , Doenças do Colo/patologia , Tomada de Decisões , Procedimentos Cirúrgicos do Sistema Digestório/veterinária , Feminino , Doenças dos Cavalos/mortalidade , Doenças dos Cavalos/patologia , Cavalos , Modelos Logísticos , Masculino , Fatores de Tempo
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