RESUMO
A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11), GWA scan; P = 1.8x10(-30), replication; P = 1.8x10(-39), combined; U.K. PSA: P = 6.9x10(-11)). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26) in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4); U.K. PSA: P = 8.0x10(-4); IL12B:rs6887695, U.S. PS, P = 5x10(-5) and U.K. PSA, P = 1.3x10(-3)) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2x10(-6) for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2x10(-5) for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9x10(-5) for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis).
Assuntos
Artrite Psoriásica/genética , Artrite Psoriásica/imunologia , Psoríase/genética , Psoríase/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoimunidade/genética , Estudos de Casos e Controles , Criança , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 4/genética , Estudos de Coortes , Feminino , Genes MHC Classe I , Predisposição Genética para Doença , Genoma Humano , Humanos , Subunidade p40 da Interleucina-12/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genéticaRESUMO
INTRODUCTION: While annual influenza vaccination of healthcare workers (HCWs) is recommended, uptake is often suboptimal. We sought to evaluate influenza vaccination uptake by HCWs in Victorian public healthcare facilities, where non-mandatory programs are used. METHODS: All participating facilities completed an annual survey (2014-2019) recording HCW influenza vaccination status. Uptake in high-risk departments (emergency and intensive care units) was evaluated for the 2019 season. RESULTS: The proportion of vaccinated HCWs increased annually, from 72.2% (2014) to 87.7% (2019), with pre-set targets generally achieved. In 2019, 110,324 HCWs in 107 facilities were vaccinated (87.7%). Of those without documented vaccination, 7591 (6.0%) declined and 7906 (6.3%) had unknown status. Uptake was higher in high-risk departments (91.4%). CONCLUSION: Increasing annual influenza vaccination uptake by HCWs in Victorian public healthcare facilities has been achieved in the context of performance monitoring targets. Small proportions declined or had unknown status. Future policies should focus on these HCWs.
Assuntos
Vacinas contra Influenza , Influenza Humana , Atitude do Pessoal de Saúde , Pessoal de Saúde , Humanos , Influenza Humana/prevenção & controle , Inquéritos e Questionários , VacinaçãoRESUMO
BACKGROUND: In the last decade, human papillomavirus (HPV) testing has been evaluated extensively for cervical screening, with studies finding increased sensitivity compared to cytology. Another advantage of HPV based-screening is the ability to test vaginal samples that can be collected by women themselves. Self-collection has the potential to extend cervical screening coverage by increasing participation rates, particularly among women who are under-screened or have never screened. This could have a significant impact on cervical cancer prevention, as the majority of invasive cervical cancer cases occur among under-screened women. Both the Netherlands and Australia have transitioned their national programs from cytology to HPV as the primary screening test and both countries include a pathway for self-collection. OBJECTIVES: We evaluated the relative sensitivity for HPV detection of self-collection compared with practitioner-collected cervical specimens in the context of the Australian National Cervical Screening Program (NCSP). STUDY DESIGN: 303 women aged ≥18 years attending a single tertiary referral centre took their own sample using a flocked-swab, and then had a practitioner-collected sample taken at colposcopy. All samples were tested at a single laboratory on the six PCR-based HPV assays which can be utilised in the NCSP; Roche cobas 4800 and cobas, Abbott RealTime, BD Onclarity, Cepheid Xpert, and Seegene Anyplex. RESULTS: HPV16/18 results had high observed agreement between self- and practitioner-collected samples on all assays (range: 0.94-0.99), with good agreement for non-HPV16/18 oncogenic HPV types (range: 0.64-0.73). CONCLUSIONS: Self-collection for HPV-based cervical screening shows good concordance and relative sensitivity when compared to practitionercollected samples across assays in the NCSP.
Assuntos
Detecção Precoce de Câncer/métodos , Infecções por Papillomavirus/diagnóstico , Manejo de Espécimes/métodos , Vagina/virologia , Alphapapillomavirus/isolamento & purificação , Colposcopia/normas , DNA Viral/isolamento & purificação , Feminino , Humanos , Países Baixos , Médicos , Kit de Reagentes para Diagnóstico , Sensibilidade e Especificidade , Centros de Atenção Terciária , Adulto Jovem , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/virologiaRESUMO
OBJECTIVE: To test the hypothesis that three changes in the early management of extremely low birth weight (ELBW) neonates would decrease the incidence of extra-uterine growth restriction (EUGR) by 25%. The three early management practice changes (EMPC) included surfactant at delivery followed by immediate extubation to nasal continuous positive airway pressure (CPAP), decreased oxygen exposure and early parenteral amino acids. STUDY DESIGN: Historical cohort study of preterm infantsAssuntos
Medicina Baseada em Evidências
, Recém-Nascido de Peso Extremamente Baixo ao Nascer/crescimento & desenvolvimento
, Doenças do Prematuro/terapia
, Terapia Intensiva Neonatal/métodos
, Aminoácidos/administração & dosagem
, Peso ao Nascer
, Estudos de Coortes
, Pressão Positiva Contínua nas Vias Aéreas
, Estudos Transversais
, Feminino
, Idade Gestacional
, Humanos
, Recém-Nascido
, Doenças do Prematuro/epidemiologia
, Masculino
, Oxigênio/sangue
, Nutrição Parenteral Total
, Surfactantes Pulmonares/administração & dosagem
, Resultado do Tratamento
RESUMO
We have isolated an isoform of the protein activator of lipoprotein lipase, apolipoprotein C-II, from the very low density lipoproteins of four patients of African ancestry with hypertriglyceridemia and eruptive or pedunculated xanthomata. This protein, which we designate apolipoprotein C-II2, differs from the previously recognized species, which we denote apolipoprotein C-II1, by substitution of glutamine for lysine at residue 55, a mutation which would require only a single-base substitution in the structural gene for apolipoprotein C-II1. Each of the patients in whom apolipoprotein C-II2 was found had approximately equal amounts of apolipoprotein C-II1 and apolipoprotein C-II2 among the apoproteins of the very low density lipoproteins, suggesting that the structural genes for these proteins are allelic. Two additional apparent heterozygotes were found among the first-degree relatives of each of two of the patients in patterns compatible with monogenic autosomal transmission. Approximately equal amounts of apolipoproteins C-II2 and C-II1 were also found by isoelectric focusing in 6 of a casual series of 50 normolipidemic blacks, but none or only trace amounts of apolipoprotein C-II2 were found in 500 samples from Caucasian subjects with hyperlipidemia. These findings suggest that this polymorphism is distributed primarily among blacks, possibly reflecting some positive Darwinian selection pressure. Whether this polymorphism has a modifying effect upon the development of hyperlipemia remains to be determined.
Assuntos
Apolipoproteínas C/genética , População Negra , Variação Genética , Hiperlipidemias/genética , Adulto , África/etnologia , Idoso , Sequência de Aminoácidos , Apolipoproteína C-II , Apolipoproteínas C/sangue , Apolipoproteínas E/genética , Brometo de Cianogênio , Feminino , Humanos , Hiperlipidemias/sangue , Focalização Isoelétrica , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos , Fenótipo , TripsinaRESUMO
The metabolism of apolipoproteins B-48 and B-100 (apo B-48 and B-100) in large triglyceride-rich lipoproteins was studied in three adults with familial dysbetalipoproteinemia (F. dys.) and compared to that of normolipidemic subjects. One Caucasian F. dys. subject was apparently homozygous for the common form of apo E-2, (Arg158----Cys), whereas the two Black subjects were homozygous for a different apo E-2 mutant (Arg145----Cys), which displays much less defective binding to cells than apo E-2 (Arg158----Cys). The lipoproteins were labeled with 125I and injected intravenously into fasted recipients. The results indicate that the terminal catabolism of triglyceride-rich lipoproteins of intestinal and hepatic origin is markedly impaired in apo E2/2 homozygotes with alleles Arg158----Cys and Arg145----Cys; despite long residence times, apo B-48 of chylomicrons and apo B-100 of large very low density lipoproteins are not converted appreciably to intermediate or low density lipoproteins in apo E2/2 homozygotes.
Assuntos
Apolipoproteínas B/sangue , Hiperlipoproteinemia Tipo III/genética , Lipoproteínas/sangue , Triglicerídeos/sangue , Idoso , Animais , Apolipoproteína B-100 , Apolipoproteína B-48 , Apolipoproteína E2 , Apolipoproteínas E/genética , Feminino , Cobaias , Humanos , Hiperlipoproteinemia Tipo III/sangue , Radioisótopos do Iodo , Cinética , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
We have previously described a disorder, normotriglyceridemic abetalipoproteinemia, that is characterized by the virtual absence of plasma low density lipoproteins and complete absence of apoB-100, but with apparently normal secretion of triglyceride-rich lipoproteins containing apoB-48. The patient's plasma lipoproteins were shown on polyacrylamide gels and by antibody mapping to have a new truncated apoB variant, apoB-50, circulating along with her apoB-48. We have found this individual to be homozygous for a single C-to-T nucleotide substitution at apoB codon 2252, which produces a premature in-frame stop codon. Thus, this is a rare example of homozygous hypobetalipoproteinemia. Electron photomicrographs revealed that the diameters of particles in the d less than 1.006 g/ml lipoprotein fraction, in both the postprandial and postabsorptive state, are bimodally distributed. The molar ratio of apoE to apoB in these particles is 3.5:1, similar to normal VLDL. The plasma LDL interval contains both spherical and cuboidal particles. Autologous reinfusion of labeled d less than 1.006 g/ml lipoproteins showed exponential disappearance from plasma, with an apparent half-removal time of 50 min, somewhat slower than for normal chylomicrons but within the normal range for VLDL. The calculated production rate for apoB was within the normal range in this subject. A very small amount of label was found briefly in the IDL fraction, but none at any time in LDL or HDL. Therefore, because LDL particles that contain apoB-50 lack the putative ligand domain of the LDL receptor, we conclude that the very low level of LDL is due to the rapid removal of the abnormal VLDL particles before their conversion to LDL can take place.
Assuntos
Abetalipoproteinemia/sangue , Lipoproteínas/sangue , Abetalipoproteinemia/genética , Apolipoproteínas B/sangue , Apolipoproteínas B/genética , Apolipoproteínas E/sangue , Sequência de Bases , Humanos , Immunoblotting , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Dados de Sequência Molecular , Mapeamento de PeptídeosRESUMO
In the two genetic forms of abetalipoproteinemia described previously, recessive abetalipoproteinemia and homozygous hypobetalipoproteinemia, all lipoproteins that normally contain apolipoprotein B are absent from plasma. We describe here a new disorder in which normal low density and very low density lipoproteins are absent, but in which triglycerides are absorbed from the intestine and chylomicrons are present in plasma. The underlying molecular defect appears to be selective deletion of the hepatogenous B-100 apolipoprotein. The B-48 apolipoprotein found in chylomicrons is spared. These findings suggest that the two species of apolipoprotein B are under separate genetic control and that low density lipoproteins are not normally derived from chylomicrons.
Assuntos
Apolipoproteínas/deficiência , Lipoproteínas LDL/deficiência , Lipoproteínas VLDL/deficiência , Triglicerídeos/sangue , Apolipoproteínas/genética , Apolipoproteínas B , Criança , Quilomícrons/metabolismo , Gorduras na Dieta/metabolismo , Feminino , Humanos , Absorção Intestinal , Peso Molecular , Fosfolipídeos/metabolismoRESUMO
The uptake and degradation of cholesterol-rich remnant lipoproteins, referred to as beta-VLDL, are shown in the present study to be mediated by LDL receptors (apoB,E(LDL) receptors), not by unique beta-VLDL receptors. Human blood monocytes cultured for 5-7 d bound apoB- and/or apoE-containing lipoproteins from different species with affinities equivalent to those demonstrated for the receptors on cultured human fibroblasts. Low density lipoproteins competed effectively and completely with 125I-beta-VLDL for binding to and degradation by monocyte-derived macrophages. Specific polyclonal antibodies to bovine apoB,E(LDL) receptors abolished both LDL and beta-VLDL uptake by normal human monocyte-macrophages. Immunoblots of monocyte-macrophage extracts with these antibodies revealed a single protein in human macrophages with an apparent molecular weight identical to that of the apoB,E(LDL) receptor found on human fibroblasts. Like receptors on cultured human fibroblasts, the apoB,E(LDL) receptors on monocyte-macrophages responsible for 125I-beta-VLDL and 125I-LDL uptake were efficiently down regulated by preincubation of the cells with beta-VLDL or LDL. Finally, monocyte-macrophages from seven homozygous familial hypercholesterolemia subjects were unable to metabolize beta-VLDL or LDL, but demonstrated normal uptake of acetoacetylated LDL. The classic apoB,E(LDL) receptors on human monocyte-macrophages thus mediate the uptake of beta-VLDL by these cells.
Assuntos
Colesterol/metabolismo , Lipoproteínas VLDL/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Receptores de LDL/metabolismo , Adulto , Anticorpos , Células Cultivadas , Criança , Pré-Escolar , VLDL-Colesterol , Feminino , Humanos , Hipercolesterolemia/metabolismo , Imunoensaio , Lipoproteínas LDL/metabolismo , Masculino , Peso Molecular , Receptores de LDL/análise , Receptores de LDL/imunologiaRESUMO
Complete deficiency of lipoprotein lipase (LPL) causes the chylomicronemia syndrome. To understand the molecular basis of LPL deficiency, two siblings with drastically reduced postheparin plasma lipolytic activities were selected for analysis of their LPL gene. We used the polymerase chain reaction to examine the nine coding LPL exons in the two affected siblings and three relatives. DNA sequence analysis revealed a single nucleotide change compared with the normal LPL cDNA: a G----A substitution at nucleotide position 680. This transition caused a replacement of glutamic acid for glycine at amino acid residue 142 of the mature LPL protein. Amino acid sequence comparisons of the region surrounding glycine-142 indicated that it is highly conserved among lipases from different species, suggesting a crucial role of this domain for the LPL structure. Expression studies of the mutant LPL cDNA in COS-7 cells produced normal amounts of enzyme mass. However, the mutated LPL was not catalytically active, nor was it efficiently secreted from the cells. This established that the Gly----Glu substitution at amino acid 142 is sufficient to abolish enzymatic activity and to result in the chylomicronemia syndrome observed in these patients.
Assuntos
Hiperlipoproteinemia Tipo I/genética , Lipase Lipoproteica/genética , Sequência de Aminoácidos , Sequência de Bases , Genes , Humanos , Dados de Sequência Molecular , Mutação , Oligonucleotídeos/química , Linhagem , Reação em Cadeia da Polimerase , Relação Estrutura-AtividadeRESUMO
Detection of new ligand-defective mutations of apolipoprotein B (apoB) will enable identification of sequences involved in binding to the LDL receptor. Genomic DNA from patients attending a lipid clinic was screened by single-strand conformation polymorphism analysis for novel mutations in the putative LDL receptor-binding domain of apoB-100. A 46-yr-old woman of Celtic and Native American ancestry with primary hypercholesterolemia (total cholesterol [TC] 343 mg/dl; LDL cholesterol [LDL-C] 241 mg/dl) and pronounced peripheral vascular disease was found to be heterozygous for a novel Arg3531-->Cys mutation, caused by a C-->T transition at nucleotide 10800. One unrelated 59-yr-old man of Italian ancestry was found with the same mutation after screening 1,560 individuals. He had coronary heart disease, a TC of 310 mg/dl, and an LDL-C of 212 mg/dl. A total of eight individuals were found with the defect in the families of the two patients. They had an age- and sex-adjusted TC of 240 +/- 14 mg/dl and LDL-C of 169 +/- 10 mg/dl. This compares with eight unaffected family members with age- and sex-adjusted TC of 185 +/- 12 mg/dl and LDL-C of 124 +/- 12 mg/dl. In a dual-label fibroblast binding assay, LDL from the eight subjects with the mutation had an affinity for the LDL receptor that was 63% that of control LDL. LDL from eight unaffected family members had an affinity of 91%. By way of comparison, LDL from six patients heterozygous for the Arg3500-->Gln mutation had an affinity of 36%. The percentage mass ratio of the defective Cys3531 LDL to normal LDL was 59:41, as determined using the mAb MB19 and dynamic laser light scattering. Thus, the defective LDL had accumulated in the plasma of these patients. Using this mass ratio, it was calculated that the defective Cys3531 LDL particles bound with 27% of normal affinity. Deduced haplotypes using 10 apoB gene markers showed the Arg3531-->Cys alleles to be different in the two kindreds and indicates that the mutations arose independently. The Arg3531-->Cys mutation is the second reported cause of familial ligand-defective apoB.
Assuntos
Apolipoproteínas B/genética , Mutação Puntual , Adulto , Sequência de Aminoácidos , Apolipoproteínas B/metabolismo , Arginina/genética , Arteriosclerose/genética , Sequência de Bases , Colesterol/sangue , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Hipercolesterolemia/genética , Indígenas Norte-Americanos , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Polimorfismo Conformacional de Fita Simples , Ligação Proteica , Receptores de LDL/genética , Receptores de LDL/metabolismo , População BrancaRESUMO
The freshly ovulated ovum in avian species is surrounded by a protein layer called the inner perivitelline layer (IPVL). The IPVL contains zona pellucida proteins and 6 distinct zona pellucida genes have been identified (ZPA, ZPB1, ZPB2, ZPC, ZPD and ZPX1) in the chicken. In the present research, the expression of the mRNA for ZPA, ZPB2, and ZPX1 was investigated in 2 lines of turkey hens selected for either increased egg production (E line) or increased body weight (F line). Theca and granulosa cell expression of the mRNA for ZPA and ZPB2 was also investigated in hierarchical and prehierarchical follicles from broiler breeder hens. Granulosa tissue was collected from F1 through F4 and F1 through F10 follicles in E line and F line hens, respectively. A one cm2 section of the granulosa layer around the germinal disc (GD) and an equivalent sized nongerminal disc (NGD) area was also collected from the F1 and F2 follicles from other hens from each genetic line. Granulosa and theca tissue was collected from hierarchical and prehierarchical follicles of broiler breeder hens. Total RNA was extracted from the samples. Minor groove-binding probes and primers for detecting ZPA, ZPB2, and ZPX1, were made for real-time PCR analyses. Expression of ZPA, ZPB2, and ZPX1 was detected in all follicle sizes from both genetic lines of hens. No significant differences in ZPA and ZPX1 mRNA expression were detected between the GD and NGD granulosa cells. However, the expression of the mRNA for ZPB2 was significantly greater in the GD granulosa cells when compared to the NGD granulosa cells in F1 and F2 follicles from E line and F line hens. In broiler breeder hens, the mRNA expression of ZPA and ZPB2 was greatest in the smallest prehierarchical follicles. The results suggest that higher expression of ZPB2 in the germinal disc area may be important for the preferential binding of sperm to this region of the IPVL.
Assuntos
Proteínas Aviárias/genética , Expressão Gênica , Perus/genética , Glicoproteínas da Zona Pelúcida/genética , Animais , Proteínas Aviárias/metabolismo , Feminino , Células da Granulosa/metabolismo , Folículo Ovariano/crescimento & desenvolvimento , Folículo Ovariano/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Perus/crescimento & desenvolvimento , Perus/metabolismo , Glicoproteínas da Zona Pelúcida/metabolismoRESUMO
OBJECTIVES: This study sought to determine the relationship of lipoprotein(a) (Lp(a)) and other cardiac risk factors to coronary atherosclerosis as measured by calcification of coronary arteries in asymptomatic postmenopausal women. BACKGROUND: Lipoprotein(a) is considered a risk factor for coronary heart disease. Coronary calcium deposition is believed to be a useful noninvasive marker of coronary atherosclerosis in women. However, to our knowledge, there are no reports of the relationship of Lp(a) to coronary calcium in postmenopausal women. METHODS: In 178 asymptomatic postmenopausal women (64 +/- 8 years), we measured Lp(a) and other cardiac risk factors: age, hypertension, diabetes, low-density lipoprotein cholesterol, smoking status, body mass index, physical activity level and duration of hormone replacement therapy. Electron-beam computed tomography was done to measure coronary calcium (calcium score). We analyzed the relationship between calcium score and cardiac risk factors using multivariate analysis. RESULTS: Although calcium score correlated with traditional risk factors of age, diabetes, hypertension and smoking, it did not correlate with Lp(a) in the asymptomatic postmenopausal women. Similar multivariate analyses were done in the subjects age >60 years and in the subjects with significant coronary calcium deposit (calcium score > or =50). These analyses also have failed to show an association of levels of Lp(a) with coronary calcium deposits. CONCLUSIONS: We conclude that in asymptomatic postmenopausal women, Lp(a) levels do not correlate with coronary atherosclerosis as measured by coronary calcium deposits.
Assuntos
Calcinose/metabolismo , Cálcio/metabolismo , Doença da Artéria Coronariana/etiologia , Vasos Coronários/metabolismo , Lipoproteína(a)/metabolismo , Pós-Menopausa/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Índice de Massa Corporal , Calcinose/complicações , Calcinose/diagnóstico por imagem , Calcinose/epidemiologia , Colesterol/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/metabolismo , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Tomografia Computadorizada por Raios X , Triglicerídeos/sangueRESUMO
OBJECTIVES: This study sought to evaluate the extent of atherosclerosis in coronary and iliac arteries in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia, using intravascular ultrasound imaging. BACKGROUND: Intravascular ultrasound imaging provides cross-sectional tomographic views of the vessel wall and allows quantitative assessment of atherosclerosis. METHODS: Forty-eight nonsmoking, asymptomatic patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia underwent intravascular ultrasound imaging of the left anterior descending coronary, left main coronary and common iliac arteries. Angiography showed only minimal or no narrowing in these vessels. Intravascular ultrasound images obtained during catheter pullback underwent morphometric analysis. Plaque burden was expressed as the mean and maximal intimal index (ratio of plaque area and area within the internal elastic lamina) and as the percent of vessel surface covered by plaque. RESULTS: Intravascular ultrasound detected plaque more frequently than angiography in the left anterior descending (80% vs. 29%, respectively), left main (44% vs. 16%) and iliac arteries (33% vs. 27%). Plaque burden was higher in the left anterior descending (mean intimal index [+/- SD] 0.25 +/- 0.16) than in the left main (0.11 +/- 0.16, p < 0.001) and iliac arteries (0.02 +/- 0.04, p < 0.001). Angiography detected lumen narrowing only in coronary arteries with a maximal intimal index > or = 0.42 (left anterior descending artery) and > or = 0.43 (left main artery). The area within the internal elastic lamina increased with plaque area in the left anterior descending (r = 0.82, p < 0.001) and left main arteries (r = 0.53, p < 0.001). By stepwise multiple regression analysis, the strongest predictor for plaque burden in the left anterior descending artery was the level of high density lipoprotein (HDL) cholesterol and total/HDL cholesterol ratio for the left main artery. CONCLUSIONS: In patients with heterozygous familial hypercholesterolemia and familial combined hyperlipidemia, extensive coronary plaque is present despite minimal or no angiographic changes. Compensatory vessel enlargement and diffuse involvement with eccentric plaque may account for the lack of angiographic changes. Levels of HDL cholesterol and total/HDL cholesterol ratio are far more powerful predictors of coronary plaque burden than are low density lipoprotein cholesterol levels in these patients with early, asymptomatic disease.
Assuntos
Arteriosclerose/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Hiperlipidemia Familiar Combinada/complicações , Hiperlipoproteinemia Tipo II/complicações , Ultrassonografia de Intervenção , Adulto , Idoso , Arteriosclerose/complicações , HDL-Colesterol/sangue , Angiografia Coronária , Doença da Artéria Coronariana/complicações , Vasos Coronários/diagnóstico por imagem , Feminino , Humanos , Artéria Ilíaca/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de RiscoRESUMO
Both the long and short arms of chromosome 18 have been consistently identified as potential locations for schizophrenia and bipolar affective disorder susceptibility genes. We previously described the identification of two independent pericentric inversions of chromosome 18 [inv(18)(p11.31;q21.2) and inv(18)(p11.31;q21.1)] occurring in two small families in which carriers have been diagnosed with schizophrenia and bipolar affective disorder, respectively. Using fluorescence in situ hybridization on patient metaphase chromosomes we have identified the locations of all four chromosome breakpoints in the inversion carriers. Neither pericentric inversion results in a direct gene disruption. However, each inversion breakpoint has the potential to perturb local gene expression by position effect or by the separation of important regulatory (enhancer) sequences from the core gene sequences. Five genes in the localities of the breakpoints have been identified as good candidates for the genetic basis of psychiatric illness in these families; TTMA, a novel membrane spanning protein; TCF4, a basic helix-loop-helix transcription factor; DLGAP1, an interactor of the PSD-95 synaptic protein; and ARKL1 and ARKL2, novel members of the ubiquitin ligase gene family.
Assuntos
Inversão Cromossômica/genética , Cromossomos Humanos Par 18 , Transtornos Psicóticos/genética , Sequência de Aminoácidos , Sequência de Bases , Portador Sadio , Mapeamento Cromossômico , Sequência Consenso , Primers do DNA , Família , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
OBJECTIVE: Infant mortality among extremely preterm infants (22 to 28 weeks gestation) varies considerably by gestational age. The reduction in mortality over a 20-year period, when examined in gestational age week increments, may give a more precise estimate of progress or lack thereof in caring for these infants and provide information to better inform practitioners and parents of the risk of mortality among these small infants. The objective of this analysis is to examine infant mortality (birth to 365 days) by week of gestation for infants 22 to 28 weeks gestation comparing mortality rates, adjusting for maternal and infant birth characteristics, among US births for the years 1990, 2000 and 2010. STUDY DESIGN: US vital statistics period-linked birth and infant death certificate files for the years 1990, 2000 and 2010 were used. Maternal and infant characteristics for births at 22 to 28 weeks were abstracted from the files. A trimming procedure was used to remove records that had birth weights that exceeded the interquartile range of birth weights for a given week of gestational age. Infant mortality rates were calculated, and adjusted odds ratios for mortality were generated using logistic regression models. RESULT: A total of 15,593 live births, 22 to 28 weeks gestation were available for the year 1990; 17,095 for the year 2000; and 14,721 for the year 2010. Infant mortality rates ranged from 904 per 1000 live births at 22 weeks gestation in 1990, to 835 in 2000, to 866 in 2010. Across all gestational age groups there was an adjusted reduction in the odds ratio for mortality of ~50% from 1990 to the year 2000. However, between 2000 and 2010 there was no significant reduction in infant mortality except at 25 weeks gestation (adjusted odds ratio=0.81, 95% confidence interval=0.70, 0.93). CONCLUSION: Despite a significant reduction in infant mortality among extremely preterm infants between the years 1990 and 2000, there has been little progress in reducing mortality between the years 2000 and 2010.
Assuntos
Idade Gestacional , Mortalidade Infantil/tendências , Lactente Extremamente Prematuro , Peso ao Nascer , Feminino , Humanos , Lactente , Recém-Nascido , Nascido Vivo , Modelos Logísticos , Masculino , Razão de Chances , Estados Unidos/epidemiologiaRESUMO
Indoramin is an alpha 1-adrenergic antagonist vasodilator of potential value in heart failure. We measured hemodynamics and exercise capacity in 12 patients with heart failure, before and after 1 week of indoramin dosing, 75 mg b.i.d. Maximal hemodynamic effects 2 hours after the first dose of indoramin consisted of reduced mean systemic arterial pressure from 96.0 +/- 15.3 to 87.9 +/- 15.3 mm Hg (P less than 0.05) and pulmonary wedge pressure from 23.6 +/- 7.8 to 16.9 +/- 6.6 mm Hg (P less than 0.001). Heart rate, cardiac index, and total systemic resistance did not change acutely after indoramin, but after 1 week mean systemic arterial pressure was still reduced whereas cardiac index fell from 2.69 +/- 0.38 to 2.32 +/- 0.44 L/min/m2 (P less than 0.05) and total systemic resistance rose from 20.4 +/- 2.8 to 21.9 +/- 4.0 U (P less than 0.1). After 1 week maximal exercise oxygen uptake fell from 16.8 +/- 5.6 to 12.5 +/- 3.5 ml/min/kg (P less than 0.02). This limited observation suggests that indoramin is a predominant venodilator acutely in patients with heart failure but that despite this effect it may worsen functional capacity and hemodynamics during continuous dosing in these patients.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Indóis/efeitos adversos , Indoramina/efeitos adversos , Esforço Físico , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Doença Crônica , Feminino , Humanos , Indoramina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pressão Propulsora Pulmonar/efeitos dos fármacos , Fatores de Tempo , Resistência Vascular/efeitos dos fármacosRESUMO
Using a method that measures plasma protein-bound 1/2 cystine, plasma free cyst(e)ine, and urine free cyst(e)ine, we have observed that infants receiving total parenteral nutrition supplemented with cysteine-HCl have significantly higher plasma and urine free cyst(e)ine concentrations (11.3 +/- 3.4 microns/dl and 47.2 +/- 24.0 microns/dl, means +/- SD) than when 1/2 cystine concentrations are measured by automated amino acid analysis (7.4 +/- 2.0 microns/dl, plasma and 25.0 +/- 7.0 microns/dl, urine). These data suggest that both the sulfhydryl and disulfide form of cyst(e)ine must be measured to assess the effect of cysteine-HCl supplemented total parenteral nutrition.
Assuntos
Cisteína/análise , Nutrição Parenteral Total , Nutrição Parenteral , Química Orgânica , Cisteína/sangue , Cisteína/urina , Humanos , Concentração de Íons de Hidrogênio , Recém-Nascido de Baixo Peso , Recém-Nascido , Fenômenos de Química OrgânicaRESUMO
Using a method developed to measure plasma protein-bound 1/2-cystine, we have observed that the metabolic state can affect the distribution of plasma cyst(e)ine between the bound and the free form. In five patients with homocyst(e)inemia, 1/2-homocystine was found to have replaced virtually all the cysteine normally present on sulfhydryl-binding sites of plasma proteins. The majority of the cyst(e)ine measured in the plasma of these patients (6.9 +/- 2.4 mumol/dl, mean +/- SD) was present in the form of a mixed disulfide with 1/2-homocystine (5.4 +/- 0.9 mumol/dl) rather than being free in the plasma or bound to plasma proteins.
Assuntos
Cisteína/sangue , Cistina/sangue , Homocisteína/sangue , Homocistina/sangue , Homocistinúria/sangue , Proteínas Sanguíneas/metabolismo , Feminino , Humanos , Masculino , Metionina/sangue , Ligação ProteicaRESUMO
OBJECTIVE: To determine if preterm infants are at greater risk for sudden infant death syndrome (SIDS) than term infants and to determine if the postconceptional age of SIDS deaths varies by gestational age at birth. METHODS: A cohort analysis was conducted using data from the 1987 United States' Birth Cohort Linked Birth/Infant Death Certificate tapes. SIDS was defined as the death of any infant who was > 24 weeks gestation at birth; weighed > 500 g at birth; was assigned an International Classification of Diseases-9th Revision (ICD-9) underlying cause of death of 7980; and had an autopsy. RESULTS: The overall SIDS rate using our definition was 1.20 deaths/1000 live births. The SIDS rates by gestational age categories of 24 to 28 weeks, 29 to 32 weeks, 33 to 36 weeks, and 37 or more weeks were 3.52, 3.01, 2.27, and 1.06 deaths/1000 live births, respectively. Because of misclassification of gestational age among the most preterm infants, a restricted analysis was conducted on SIDS victims whose gestational ages fell within cutoff values derived from a methodology that excluded gestational age assessments assumed to be invalid. This subgroup analysis showed a mean (standard deviates) postconceptional age of death for SIDS for infants of 24 to 28 weeks, 29 to 32 weeks, and 33 to 36 weeks gestation to be 45.8 (8.3), 47.3 (8.6), and 48.0 (8.3) weeks, respectively, compared with 52.3 (8.5) weeks for term infants (ANOVA P = .0001). CONCLUSIONS: We infer from this analysis that preterm infants are at higher risk for SIDS than term infants, and that the postconceptional age of peak vulnerability for SIDS may differ by 4 to 6 weeks between preterm and term infants.