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1.
Mol Genet Metab ; 129(2): 98-105, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31383595

RESUMEN

The outcome of 110 patients with paediatric onset mucopolysaccharidosis II (MPS II) since the commercial introduction of enzyme replacement therapy (ERT) in England in 2007 is reported. Median length of follow up was 10 years 3 months (range = 1 y 2 m to 18 years 6 month). 78 patients were treated with ERT, 18 had no ERT or disease modifying treatment 7 had haematopoietic stem cell transplant, 4 experimental intrathecal therapy and 3 were lost to follow up. There is clear evidence of improved survival (median age of death of ERT treated (n = 16) = 15.13 years (range = 9.53 to 20.58 y), and untreated (n = 17) = 11.43 y (0.5 to 19.13 y) p = .0005). Early introduction of ERT improved respiratory outcome at 16 years, the median FVC (% predicted) of those in whom ERT initiated <8 years = 69% (range = 34-86%) and 48% (25-108) (p = .045) in those started >8 years. However, ERT appears to have minimal impact on hearing, carpal tunnel syndrome or progression of cardiac valvular disease. Cardiac valvular disease occurred in 18/46 (40%), with progression occurring most frequently in the aortic valve 13/46 (28%). The lack of requirement for neurosurgical intervention in the first 8 years of life suggests that targeted imaging based on clinical symptomology would be safe in this age group after baseline assessments. There is also emerging evidence that the neurological phenotype is more nuanced than the previously recognized dichotomy of severe and attenuated phenotypes in patients presenting in early childhood.


Asunto(s)
Terapia de Reemplazo Enzimático , Mucopolisacaridosis II/tratamiento farmacológico , Adolescente , Niño , Preescolar , Recolección de Datos , Progresión de la Enfermedad , Inglaterra , Estudios de Seguimiento , Humanos , Lactante , Mucopolisacaridosis II/mortalidad , Fenotipo , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento
2.
J Hum Genet ; 63(6): 707-716, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29618761

RESUMEN

Seven subunits of the mitochondrial contact site and cristae junction (CJ) organizing system (MICOS) in humans have been recently described in function and structure. QIL1 (also named MIC13) is a small complex that is crucial for the maintenance and assembling of MICOS. A novel mutation of an essential splice site in the C19orf70 gene encoding QIL1 induces severe mitochondrial encephalopathy, hepatopathy and lactate acidosis consistent with psychomotor retardation. In addition, bilateral kidney stones were observed. Disassembly of MICOS complex subunits displays lack of MIC10-MIC26-MIC27-QIL1 subcomplex, resulting in aberrant cristae structure and a loss of cristae junctions and contact sites. In liver and muscle tissue, the activity of the respiratory chain complexes (OXPHOS) was severely impaired. Defects in MICOS complex do not only affect mitochondrial architecture, but also mitochondrial fusion, metabolic signalling, lipid trafficking and cellular electric homeostasis.


Asunto(s)
Genes Letales , Hepatopatías/genética , Proteínas de la Membrana/genética , Mitocondrias/metabolismo , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Mutación , Desempeño Psicomotor , Acidosis Láctica/complicaciones , Encéfalo/diagnóstico por imagen , Transporte de Electrón , Resultado Fatal , Femenino , Humanos , Lactante , Recién Nacido , Cálculos Renales/complicaciones , Hígado/metabolismo , Hepatopatías/complicaciones , Hepatopatías/fisiopatología , Imagen por Resonancia Magnética , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/diagnóstico por imagen , Encefalomiopatías Mitocondriales/fisiopatología , Músculos/metabolismo , Sistemas de Lectura Abierta , Fosforilación Oxidativa , Sitios de Empalme de ARN
3.
J Inherit Metab Dis ; 38(5): 931-40, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25778940

RESUMEN

Congenital disorders of glycosylation (CDG) are a group of hereditary metabolic diseases characterized by abnormal glycosylation of proteins and lipids. Often, multisystem disorders with central nervous system involvement and a large variety of clinical symptoms occur. The main characteristics are developmental delay, seizures, and ataxia. In this paper we report the clinical and biochemical characteristics of a 5-year-old girl with a defective galactosylation of N-glycans, resulting in developmental delay, muscular hypotonia, epileptic seizures, inverted nipples, and visual impairment. Next generation sequencing revealed a de novo mutation (c.797G > T, p.G266V) in the X-chromosomal gene SLC35A2 (solute carrier family 35, UDP-galactose transporter, member A2; MIM 300896). While this mutation was found heterozygous, random X-inactivation of the normal allele will lead to loss of normal SLC35A2 activity in respective cells. The functional relevance of the mutation was demonstrated by complementation of UGT-deficient MDCK-RCA(r) and CHO-Lec8 cells by normal UGT-expression construct but not by the mutant version. The effect of dietary galactose supplementation on glycosylation was investigated, showing a nearly complete normalization of transferrin glycosylation.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Trastornos Congénitos de Glicosilación/terapia , Proteínas de Transporte de Monosacáridos/genética , Animales , Células CHO , Preescolar , Cricetinae , Cricetulus , Análisis Mutacional de ADN , Perros , Femenino , Galactosa/uso terapéutico , Humanos , Células de Riñón Canino Madin Darby , Proteínas de Transporte de Monosacáridos/deficiencia , Fenotipo
4.
Mol Genet Metab ; 108(1): 82-4, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23219289

RESUMEN

Niemann Pick Type C2 (NPC2) is a rare autosomal recessive disease caused by mutations in the NPC2 gene (OMIM 601015). Clinically, NPC2 presents in most cases in the neonatal period with inflammatory lung disease, which may lead to death in the first year. If patients survive the neonatal period, they may develop a severe neurological disease. Here we present the developmental and neurological follow up at 5 years of age of a child with NPC2 successfully treated with allogenic bone marrow transplantation (BMT) at the age of 16 months. A homozygous p.E20X sequence variation previously associated with a severe phenotype was identified. In contrast to the previously reported patients with the same mutations, our patient has no respiratory compromise and has made some developmental progress (especially gross motor), though is significantly delayed (particularly in speech and language). Haematopoietic stem cell transplantation (HSCT) could be considered for patients with this mutation as long as performed early in the course of the disease.


Asunto(s)
Trasplante de Médula Ósea , Enfermedad de Niemann-Pick Tipo C/cirugía , Resultado Fatal , Humanos , Lactante , Recién Nacido , Enfermedad de Niemann-Pick Tipo C/fisiopatología , Trasplante Homólogo
5.
Nutr Metab Cardiovasc Dis ; 23(8): 732-6, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22795295

RESUMEN

BACKGROUND AND AIM: The complete absence of the lysosomal acid lipase (LAL) enzyme function causes Wolman's Disease that is fatal within the first six months of life. Subtotal defects cause Cholesteryl ester storage disease (CESD), an autosomal recessive disorder leading to hepatic steatosis, fibrosis, micronodular cirrhosis, combined hyperlipidemia with low HDL-cholesterol, increased risk for atherosclerosis, premature death. Since the frequency of the Exon 8 splice junction mutation (c.894 G > A, E8SJM), the CESD leading mutation, is not rare in the general population (allele frequency 0.0025), we investigated the impact of this mutation on serum lipid profile in E8SJM carriers. METHODS AND RESULTS: We collected E8SJM carriers both form genetic study-population analysis and from Outpatient Lipid Clinics and then we assessed their serum lipid profile. We found thirteen individuals heterozygote for E8SJM. Most of them were Germans, three Spanish and two Italian. We found a significant increase in total cholesterol levels in both sexes with E8SJM mutation, leading to a significant increase in LDL cholesterol in males. CONCLUSIONS: Our results show that LAL E8SJM carriers have an alteration in lipid profile with a Polygenic Hypercholesterolemia phenotype, leading to an increase in cardiovascular risk profile.


Asunto(s)
Colesterol/sangre , Heterocigoto , Mutación , Esterol Esterasa/genética , Enfermedades Cardiovasculares/genética , Estudios de Casos y Controles , Femenino , Alemania , Humanos , Italia , Masculino , Fenotipo , Factores de Riesgo , España , Población Blanca
6.
Nat Genet ; 20(1): 96-8, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9731541

RESUMEN

A low level of high density lipoprotein (HDL) cholesterol is a strong predictor of ischaemic heart disease (IHD) and myocardial infarction. One cause of low HDL-cholesterol is Tangier disease (TD), an autosomal codominant inherited condition first described in 1961 in two siblings on Tangier Island in the United States of America. Apart from low HDL-cholesterol levels and an increased incidence of atherosclerosis, TD is characterized by reduced total cholesterol, raised triglycerides, peripheral neuropathy and accumulation of cholesteryl esters in macrophages, which causes enlargement of the liver, spleen and tonsils. In contrast to two other monogenic HDL deficiencies in which defects in the plasma proteins apoA-I and LCAT interfere primarily with the formation of HDL (refs 7-10), TD shows a defect in cell signalling and the mobilization of cellular lipids. The genetic defect in TD is unknown, and identification of the Tangier gene will contribute to the understanding of this intracellular pathway and of HDL metabolism and its link with IHD. We report here the localization of the genetic defect in TD to chromosome 9q31, using a genome-wide graphical linkage exclusion strategy in one pedigree, complemented by classical lod score calculations at this region in a total of three pedigrees (combined lod 10.05 at D9S1784). We also provide evidence that TD may be due to a loss-of-function defect.


Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 9 , Ligamiento Genético , Enfermedad de Tangier/genética , Consanguinidad , Femenino , Homocigoto , Humanos , Escala de Lod , Masculino , Modelos Genéticos , Linaje , Lugares Marcados de Secuencia
7.
Nat Genet ; 22(4): 352-5, 1999 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10431238

RESUMEN

Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island. This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals. Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families. We report here refining of our previous linkage of the TD gene to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1). We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes. In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype. An in-frame insertion-deletion in exon 12 was found in the second family. Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Glicoproteínas/genética , Mutación , Enfermedad de Tangier/genética , Transportador 1 de Casete de Unión a ATP , Secuencia de Aminoácidos , Apolipoproteínas E/sangre , Secuencia de Bases , Cromosomas Humanos Par 9 , Exones , Femenino , Biblioteca de Genes , Marcadores Genéticos , Humanos , Lipoproteínas HDL , Masculino , Modelos Biológicos , Modelos Genéticos , Datos de Secuencia Molecular , Linaje
8.
Mol Genet Metab ; 105(4): 634-41, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22304930

RESUMEN

Congenital disorders of glycosylation (CDG) are caused by enzymatic defects of the formation or processing of lipid-linked oligosaccharides and glycoproteins. Since the majority of proteins is glycosylated, a defect in a singular CDG enzyme leads to a multisytemic disease with secondary malfunction of thousands of proteins. CDG-Ij (DPAGT1-CDG) is caused by a defect of the human DPAGT1 (UDP-GlcNAc: Dolichol Phosphate N-Acetylglucosamine-1-Phosphotransferase), catalyzing the first step of N-linked glycosylation. So far the clinical phenotype of only one CDG-Ij patient has been described. The patient showed severe muscular hypotonia, intractable seizures, developmental delay, mental retardation, microcephaly and exotropia. Molecular studies of this patient revealed the heterozygous mutation c.660A>G (Y170C; paternal) in combination with an uncharacterized splicing defect (maternal). Two further mutations, c.890A>T (I297F) and c.162-8G>A as a splicing defect were detected when analyzing DPAGT1 in two affected siblings of a second family. We report two new patients with the novel homozygous mutation, c.341C>G (A114 G), causing a severe clinical phenotype, characterized by hyperexcitability, intractable seizures, bilateral cataracts, progressive microcephaly and muscular hypotonia. Both our patients died within their first year of life. With the discovery of this novel mutation and a detailed clinical description we extend the clinical features of CDG-Ij in order to improve early detection of this disease.


Asunto(s)
Trastornos Congénitos de Glicosilación/enzimología , Trastornos Congénitos de Glicosilación/genética , Mutación/genética , Enfermedades Raras/enzimología , Enfermedades Raras/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Adulto , Secuencia de Aminoácidos , Células Cultivadas , Cromatografía Líquida de Alta Presión , Electroforesis en Gel de Poliacrilamida , Femenino , Fibroblastos/citología , Fibroblastos/enzimología , Glicosilación , Homocigoto , Humanos , Inmunoprecipitación , Recién Nacido , Lipopolisacáridos/metabolismo , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Piel/citología , Piel/enzimología
9.
Mol Genet Metab ; 105(4): 642-51, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22304929

RESUMEN

Congenital disorders of glycosylation (CDG) are caused by a dysfunction of glycosylation, an essential step in the manufacturing process of glycoproteins. This paper focuses on a 6-year-old patient with a new type of CDG-I caused by a defect of the steroid 5α reductase type 3 gene (SRD5A3). The clinical features were psychomotor retardation, pathological nystagmus, slight muscular hypotonia and microcephaly. SRD5A3 was recently identified encoding the polyprenol reductase, an enzyme catalyzing the final step of the biosynthesis of dolichol, which is required for the assembly of the glycans needed for N-glycosylation. Although an early homozygous stop-codon (c.57G>A [W19X]) with no functional protein was found in the patient, about 70% of transferrin (Tf) was correctly glycosylated. Quantification of dolichol and unreduced polyprenol in the patient's fibroblasts demonstrated a high polyprenol/dolichol ratio with normal amounts of dolichol, indicating that high polyprenol levels might compete with dolichol for the initiation of N-glycan assembly but without supporting normal glycosylation and that there must be an alternative pathway for dolichol biosynthesis.


Asunto(s)
3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , Trastornos Congénitos de Glicosilación/enzimología , Trastornos Congénitos de Glicosilación/genética , Proteínas de la Membrana/genética , Mutación/genética , Pentanoles/metabolismo , Células Cultivadas , Cromatografía Líquida de Alta Presión , Trastornos Congénitos de Glicosilación/diagnóstico , Dolicoles/metabolismo , Electroforesis en Gel de Poliacrilamida , Femenino , Fibroblastos , Prueba de Complementación Genética , Glicosilación , Homocigoto , Humanos , Inmunoprecipitación , Recién Nacido , Focalización Isoeléctrica , Masculino , Linaje
10.
Orphanet J Rare Dis ; 17(1): 193, 2022 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-35550173

RESUMEN

BACKGROUND: Lysosomal acid lipase deficiency (LALD) is an ultra-rare, inherited metabolic disease within the category of lysosomal storage disorders, affecting an infant's ability to metabolise cholesterol. Developments in treatment, including Enzyme Replacement Therapy, have proven successful, with some children living for a number of years with treatment, although the future still remains unknown. The aim of this study was to explore the lived experiences of parents of children with LALD. MAIN TEXT: Participants were recruited from across the United Kingdom between 2020 and 2021. Eight parents (five mothers and three fathers) whose child had a confirmed diagnosis of LALD were interviewed. Data collected from the semi-structured interviews were audio-record, transcribed and analysed using Interpretative Phenomenological Analysis (IPA). Three superordinate and nine subordinate themes emerged from the data: (1) Uncertainty-a double-edged sword (plunged into an uncertain world, living life with worry and walking the tightrope of stability), (2) Powerless against a shared battle with LALD (a helpless parent, a joint battle, protection against distress and a vulnerable parent needing help) and 3) Accepting a life with LALD (coming to terms with a diagnosis of LALD and a hidden condition). CONCLUSIONS: The findings of this study highlight that the diagnosis of LALD proves to be a very challenging and emotionally distressing time in parents' lives, with increased uncertainty about what the future will hold for their child. This study signified the importance of healthcare pathways and service provisions to support parents and their children throughout diagnosis and beyond.


Asunto(s)
Enfermedad de Wolman , Niño , Terapia de Reemplazo Enzimático , Femenino , Humanos , Lactante , Madres , Padres/psicología , Investigación Cualitativa , Enfermedad de Wolman/diagnóstico , Enfermedad de Wolman
12.
Adv Appl Microbiol ; 71: 149-84, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20378054

RESUMEN

Recent threats posed by pathogenic microorganisms in food, recreational waters, and as agents of bioterror have underscored the need for the development of more rapid, accurate, and cost-effective methods of microbial characterization and identification. This chapter focuses on the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to rapidly characterize and identify microorganisms through generation of characteristic fingerprints of intact cells. While most efforts have focused on bacteria, this technology has also been applied to fungi and viruses. Results of most studies suggest that MALDI-TOF MS can be used to rapidly and accurately characterize microorganisms. A variety of quantitative approaches have been employed in the analysis of MALDI-TOF MS fingerprints of microorganisms. The reproducibility of fingerprints of intact cells remains a primary concern and limitation associated with this approach. Protocols and instrumentation used have varied considerably and likely account for much of the variability in reproducibility reported. Key first steps to overcoming this limitation will be the development of standard approaches to quantifying reproducibility and the development of standard protocols for sample preparation and analysis.


Asunto(s)
Bacterias/clasificación , Dermatoglifia del ADN/métodos , Hongos/clasificación , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Virus/clasificación , Bacterias/genética , Hongos/genética , Reproducibilidad de los Resultados , Virus/genética
13.
JIMD Rep ; 44: 79-84, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30097991

RESUMEN

Lathosterolosis is a rare defect of cholesterol synthesis. Only four previous cases have been reported, two of whom were siblings. We report a fifth patient, with a relatively mild phenotype. He presented at 5 years of age with bilateral posterior cataracts, which were managed with lensectomies and intraocular lens implants. He also had learning difficulties, with a full-scale IQ of 64 at 11 years of age. His head circumference is between the 0.4th and 2nd centiles, and he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes). The diagnosis was established after sequencing a panel of genes associated with cataracts, which revealed compound heterozygous SC5D mutations: c.479C>G p.(Pro160Arg) and c.630C>A p.(Asp210Glu). The plasma lathosterol concentration was markedly raised at 219.8 µmol/L (control range 0.53-16.0), confirming the diagnosis. The c.630C>A p.(Asp210Glu) mutation has been reported in one previous patient, who also had a relatively mild phenotype (Ho et al., JIMD Rep 12:129-134, 2014). The mutation leads to a relatively conservative amino acid substitution, consistent with some residual enzyme activity. Our patient's family did not notice any benefit from treatment with simvastatin. In summary, milder patients with lathosterolosis may present with learning difficulties, cataracts and very subtle dysmorphism. The diagnosis will be missed unless plasma sterols are analysed or relevant genes sequenced.

14.
Eur J Clin Nutr ; 61(7): 896-905, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17228349

RESUMEN

OBJECTIVE: We investigated the serum phytosterol responses of heterozygous relatives of sitosterolemia patients to diets enriched in phytosterols or stanols. DESIGN: Randomized double-blind crossover design. SETTING: Muenster, Germany. SUBJECTS: Eight heterozygous and 13 control subjects were recruited. One heterozygote and three controls dropped out. INTERVENTIONS: Seven heterozygotes and 10 controls received daily portions of margarine containing 2 g of plant sterols, 2 g of stanols or a control margarine for 6 weeks each in a randomized order. These phases were intercepted by wash-out periods of 6 weeks each. RESULTS: Compared to the control period, serum phytosterol concentrations increased overall by more than 20% when subjects consumed the plant sterol margarine (F((1,15))=8.719, P=0.01), with no significant difference between heterozygotes (mean +14.5 (s.d. 17.2) micromol/l, +23.0%) and controls (+4.9 (9.9) micromol/l, +20.5%; F((1,15))=2.168, P=0.162), but decreased when subjects consumed the stanol-enriched margarine (F((1,15))=12.124, P=0.003), again to a similar extent in heterozygotes (-34.2 (41.2) micromol/l, -54.2%) and controls (-12.2 (9.2) micromol/l, -50.6%; F((1,15))=2.729, P=0.119). The lowest total serum concentrations of cholesterol and phytosterols were seen after the diet enriched in stanols. Serum stanol concentrations increased on this diet, but on a very low level and never exceeded 0.05% of serum cholesterol levels in any subject. CONCLUSIONS: Serum phytosterol concentrations increased only moderately in heterozygotes consuming a diet enriched in phytosterols, indicating that they retained considerable capacity to excrete phytosterols even at higher intakes.


Asunto(s)
Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/sangre , Margarina , Fitosteroles , Sitoesteroles/sangre , Adulto , Colesterol/sangre , Estudios Cruzados , Método Doble Ciego , Ésteres , Femenino , Alemania , Humanos , Masculino , Fitosteroles/administración & dosificación , Fitosteroles/sangre , Sitoesteroles/administración & dosificación , Esteroles/administración & dosificación , Esteroles/sangre
15.
JIMD Rep ; 26: 21-9, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26238249

RESUMEN

Congenital disorders of glycosylation form a rapidly growing group of inherited metabolic diseases. As glycosylation affects proteins all over the organism, a mutation in a single gene leads to a multisystemic disorder. We describe a patient with TMEM165-CDG with facial dysmorphism, nephrotic syndrome, cardiac defects, enlarged cerebral ventricles, feeding problems, and neurological involvement. Having confirmed the diagnosis via prenatal diagnostics, we were able to observe the glycosylation right from birth, finding a pathological pattern already on the first day of life. Within the next few weeks, hypoglycosylation progressed to less sialylated and then also to hypogalactosylated isoforms. On the whole, there has not been much published evidence concerning postnatal glycosylation and its adaptational process. This is the first paper reporting changes in glycosylation patterns over the first postnatal weeks in TMEM165-CDG.

16.
Int J Tuberc Lung Dis ; 19(11): 1271-5, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26467577

RESUMEN

The Ebola outbreak that started in late 2013 is by far the largest and most sustained in history. It occurred in a part of the world where pre-existing health systems were already fragile, and these deteriorated further during the epidemic due to a large number of health worker deaths; temporary or permanent closure of health facilities; non-payment of health workers; intrinsic fear of contracting or being stigmatised by Ebola among the population, which negatively influenced health-seeking behaviour; enforced quarantine of Ebola-affected communities, restricting the access of vulnerable individuals to health facilities; and late response by the international community. There are also reports of drug and consumable stockouts due to deficiencies in the procurement and supply chain as a result of overriding Ebola-related priorities. Providing tuberculosis (TB) care and achieving favourable treatment outcomes require a fully functioning health system, accurate patient tracking and high patient adherence to treatment. Furthermore, as Ebola is easily transmitted through body fluids, the use of needles-essential for TB diagnosis and treatment-needs to be avoided during an outbreak. We highlight ways in which a sustained Ebola outbreak could jeopardise TB activities and suggest pre-emptive preventive measures while awaiting operational research evidence.


Asunto(s)
Brotes de Enfermedades , Personal de Salud/psicología , Fiebre Hemorrágica Ebola/epidemiología , Tuberculosis/epidemiología , Personal de Salud/economía , Accesibilidad a los Servicios de Salud , Humanos , Investigación Operativa , Estigma Social , Tuberculosis/prevención & control
17.
Atherosclerosis ; 86(1): 55-68, 1991 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-2064636

RESUMEN

Cells with enhanced levels of collagen type I and III mRNA were identified and localized in frozen tissue sections from samples of human atherosclerotic renal and common iliac arteries by in situ hybridization using complementary 35S-labeled RNA probes. Serial sections were immunohistochemically stained for smooth muscle cells, monocytes, and differentiated macrophages. In the fibromuscular intima and in the fibrous plaques, cells with enhanced transcriptional activity were located mainly in the vicinity of differentiated macrophages. In three patients, lack of enhanced transcriptional activity in a proliferated intima was connected with complete absence of macrophages, thus indicating a quiescent stage of atherosclerosis. Immunohistochemical staining of serial sections for smooth muscle cells (SMC) revealed the presence of this cell type throughout the proliferated intima in atherosclerotic arteries including those areas in which enhanced collagen mRNAs were detected. The present results support the idea that macrophages play an important role in the activation of collagen synthesis in SMC of atherosclerotic vessel walls.


Asunto(s)
Arteriosclerosis/metabolismo , Colágeno/genética , Arteria Ilíaca/metabolismo , ARN Mensajero/metabolismo , Arteria Renal/metabolismo , Adolescente , Adulto , Anciano , Arteriosclerosis/genética , Arteriosclerosis/patología , Colágeno/metabolismo , ADN/metabolismo , Femenino , Humanos , Arteria Ilíaca/patología , Inmunohistoquímica , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Persona de Mediana Edad , Hibridación de Ácido Nucleico , Arteria Renal/patología
18.
J Histochem Cytochem ; 38(9): 1365-75, 1990 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-2387988

RESUMEN

Enhanced synthesis and deposition of extracellular matrix components, including collagen, contribute significantly to arteriosclerotic changes in the arterial vessel wall. We localized cells actively synthesizing collagen by hybridizing 35S-labeled RNA probes complementary to type I and III collagen mRNA with cytoplasmic mRNA in frozen sections of surgically removed aortic coarctations. These were chosen as a model for comparing mRNA levels in areas of high blood pressure-induced wall thickening and in unaffected post-stenotic areas. In situ hybridization revealed increased expression of type I and III collagen mRNA in intimal cells and in cells adjacent to the medial-adventitial border in the pre-stenotic part of the coarctation. In contrast, cells of the post-stenotic area showed only a very low signal. No immunohistologically detectable macrophages were seen in the pre-stenotic subendothelial areas where mRNA levels were enhanced. Higher collagen mRNA levels therefore occur in particular regions of high blood pressure-induced arterial wall thickening in the absence of macrophages. The results suggest that in situ hybridization is suitable for detection of locally occurring transcriptional activation of cells for collagens in the vessel wall.


Asunto(s)
Coartación Aórtica/metabolismo , Colágeno/genética , Citoplasma/metabolismo , ARN Mensajero/metabolismo , Adolescente , Adulto , Coartación Aórtica/patología , Arteriosclerosis/etiología , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Niño , Preescolar , Colágeno/análisis , Citoplasma/análisis , Citoplasma/ultraestructura , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Inmunohistoquímica , Masculino , Hibridación de Ácido Nucleico , ARN Mensajero/genética
19.
Thromb Res ; 77(3): 209-15, 1995 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-7740513

RESUMEN

Despite many investigations in a variety of experimental settings, uncertainty remains concerning the size of the genetic contribution to plasma fibrinogen levels. We used the polymerase chain reaction to amplify the polymorphic sites for the restriction enzymes TaqI in the alpha-fibrinogen gene and HaeIII, HindIII and BclI in the beta-fibrinogen gene. Three hundred and eighty-four male coronary heart disease patients were investigated. Two alleles for each enzyme (+ or - designating, respectively, the presence or absence of the cutting site) were detected. The HaeIII and HindIII cutting sites were in complete linkage disequilibrium. A small but significant increase in fibrinogen level was associated with the rare cutting sites of HaeIII/HindIII, BclI and TaqI. At all polymorphic sites homozygosity for the frequent alleles was associated with about 0.20 g/l lower plasma fibrinogen concentrations than heterozygosity at the respective sites (p < 0.05). The frequencies and natures of the rare alleles were as follows: TaqI (+) 0.28, HaeIII/HindIII (-) 0.22 and BclI (+) 0.17. Mean fibrinogen levels in patients heterozygous for each of the four polymorphisms were 0.47 g/l greater than in subjects homozygous for the frequent allele at each cutting site (HaeIII/HindIII + -, TaqI + -, BclI + -: fibrinogen level 3.58 g/l (n = 32); HaeIII/HindIII + +, TaqI - -, BclI - -: fibrinogen level 3.11 g/l (n = 99), p = 0.003). Each polymorphism accounted for between 0.5 and 1.4% of the overall variance in fibrinogen concentration. Together, the polymorphisms in HaeIII, HindIII and TaqI explained 5.8% of overall variance, a proportion equivalent to that explained by age, smoking and body mass index (5.5%).(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Enfermedad Coronaria/sangre , Fibrinógeno/genética , Genes , Polimorfismo de Longitud del Fragmento de Restricción , Alelos , Secuencia de Bases , Fibrinógeno/análisis , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular
20.
J Anim Sci ; 70(2): 538-46, 1992 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-1548218

RESUMEN

The effects of an asynchronous supply of fixed amounts of N and carbohydrate on bacterial growth were measured in two batch culture experiments. In Exp. 1, aqueous glucose and urea solutions were added at hourly intervals to culture flasks containing strained ruminal liquor and phosphate/bicarbonate buffer. The ratio of urea N to glucose was either constant (Synchrony, 26 mg of N/g of glucose) or increased exponentially over time (Asynchrony, .013 to 48,900 mg of N/g of glucose). After 12 h, identical quantities of glucose and urea had been added in both treatments. Bacterial population size (estimated from optical density) was greater (P less than .001) from 5 to 8 h of incubation for Synchrony than for Asynchrony, but after 12 h there was no difference (P greater than .1) between treatments. In Exp. 2, large (1 to 1.5 mm) and small (less than .5 mm) corn particles were used as slowly and rapidly degraded energy sources, with soybean meal (1 to 1.5 mm) and a papaic digest of soybean meal as sources of slowly and rapidly degraded N. At incubation times, when the ratio between total starch and N degraded was equal between treatments, bacterial population size was unaffected by the relative rate of N and OM supply. In both experiments, bacterial growth recovered quickly from transient restriction caused by deficits of N.


Asunto(s)
Bacterias/crecimiento & desarrollo , Metabolismo de los Hidratos de Carbono , Nitrógeno/metabolismo , Rumen/microbiología , Amoníaco/análisis , Animales , Tampones (Química) , Carbohidratos/análisis , Bovinos , Ácidos Grasos Volátiles/análisis , Fermentación , Glucosa/metabolismo , Concentración de Iones de Hidrógeno , Masculino , Proteínas/metabolismo , Glycine max , Almidón/metabolismo , Urea/metabolismo , Zea mays
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