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PURPOSE: GH deficit (GHD) could represent an endocrine issue in ß-Thalassemia Major (ßTM) patients. GH/IGF-1 axis has not been extensively explored in ßTM adults, so far. We aim to assess GHD and IGF-1 deficiency prevalence in ßTM adult population, focusing on the relationship with liver disease. METHODS: Cross-sectional multi-centre study conducted on 81 adult ßTM patients (44 males, mean age 41 ± 8 years) on transfusion and chelation therapy. GHD was investigated by GHRH + arginine test. IGF-1 levels, routine biochemical exams, Fibroscan, Hepatic Magnetic Resonance Imaging (MRI) and pituitary MRI were collected. RESULTS: Eighteen patients were affected by GHD and 63 were not (nGHD) according to GHRH + arginine test, while basal GH levels did not differ. GHD was associated with a higher BMI and a worse lipid profile (p < 0.05). No significant differences were observed regarding liver function between the two groups. Pituitary MRI scan was normal except for one case of empty sella. The 94.4% and 93.6% of GHD and nGHD, respectively, presented lower IGF-1 levels than the reference range, and mean IGF-1 SDS was significantly lower in GHD patients. CONCLUSION: GHD is frequent in adult ßTM patients and is associated with higher BMI and worse lipid profile. nGHD patients present lower IGF-1 levels as well. There was no relationship between IGF-1 levels and liver disease. Further, multicentric studies with larger cohorts and standardized diagnostic protocols are needed.
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Hormona de Crecimiento Humana , Talasemia beta , Adulto , Arginina , Estudios Transversales , Humanos , Factor I del Crecimiento Similar a la Insulina , Lípidos , Masculino , Persona de Mediana Edad , Talasemia beta/complicaciones , Talasemia beta/epidemiologíaRESUMEN
The COVID-19 outbreak is spreading worldwide pushing the national healthcare systems to find effective protocols to prevent contagion and to reduce the patients' mortality and the severity of long-term effects. In the absence of authorised pharmacological treatments, chloroquine, and hydroxychloroquine, which are known as anti-malaria drugs, had been widely used off-label until concerns about their efficacy/safety limited their use to hospitalized patients affected by severe COVID-19. Regardless of their clinical use, their manipulation is necessary since the pure drug substance is not always promptly available and most of the drug products available on the market are tablets designed to be ingested; no liquid dosage forms are available. These are needed for children and the enteral nutrition of inpatients of intensive care units. Considering that both chloroquine and hydroxychloroquine are BCS class I, proper procedures for purifying the preparation from the insoluble excipients may be adopted to avoid clogging of a nasogastric tube and to reduce the drug content variability in the administered doses. The data in this article indicate that compounded oral suspensions containing chloroquine and hydroxychloroquine can be filtered and/or centrifuged without altering the drug assay of the preparation.
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Cheese whey is a nutritious byproduct in the dairy industry, however, due to low commercial value, its use as a milk adulterant is a common practice not easily detected by routine analysis. In Brazil, quantification of caseinomacropeptide (CMP) index, using High Performance Liquid Chromatography (HPLC), is officially used to investigate illegal cheese whey addition to milk. Milk with CMP index above 30mg/L is considered not suitable for human consumption. The objective of this research was to report the CMP index in 185 samples of pasteurized milk, representing 73 commercial brands produced in 51 counties and ten mesoregions of the state of Minas Gerais, from 2011 to 2013 (58 samples) and 2015 to 2017 (127 samples). CMP index was considered normal (up to 30mg/L) in 75.1% of the samples. However, 21.1% presented CMP index above 75mg/L and 3.8% from 31 to 75mg/L. CMP index above 75mg/L was found in 17.4% of the samples produced during the dry season (April to September) and in 24.7% during the rainy season (October to March). These data point to the need of more efficient monitoring and inspection processes to hinder adulteration with cheese whey addition to milk.(AU)
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Péptidos , Caseínas/análisis , Leche , Pasteurización , Fraude , Brasil , Contaminación de Alimentos/análisisAsunto(s)
Terapia por Quelación , Talasemia , Humanos , Talasemia/tratamiento farmacológico , HierroRESUMEN
OBJECTIVE: To evaluate left ventricular morphology and function in a large population of patients with beta thalassaemia. DESIGN: Echo Doppler assessment of left ventricular function and correlation of cardiovascular data with haematological data. SETTING: Thalassaemia unit in a tertiary referral centre. PATIENTS: 197 young adults with beta thalassaemia, following an adequate transfusional and chelation treatment regimen, without clinical signs of cardiopulmonary involvement. The control group consisted of 213 healthy subjects. RESULTS: Left ventricular volumes, mass index, and mass/volume ratio were increased. Diastolic and systolic shapes were different, the left ventricle maintaining an ellipsoidal shape. The ejection fraction was reduced, and was < 50% in 33 patients. Stroke volume and cardiac index were increased, and systemic vascular resistance was decreased. Fractional shortening and mean velocity of circumferential shortening were decreased. Meridional end systolic and peak systolic stress were increased, as was circumferential end systolic stress. The contractile state was reduced while the functional preload index did not differ. Left ventricular diastolic function, evaluated from the mitral inflow, showed a slightly prolonged isovolumic relaxation time, increased flow velocity integrals, and an increased E/A ratio. Among the haematological data, only serum ferritin showed a weak negative correlation with left ventricular ejection fraction. The patients with the highest serum ferritin (> 2500 ng/ml) had the lowest ejection fraction. CONCLUSIONS: Patients with beta thalassaemia on an adequate transfusion and chelation treatment regimen show abnormal left ventricular remodelling with increased volumes, mass, and mass/volume ratio. Systolic chamber function and contractile state are reduced, with a slightly increased afterload. These findings seem mainly to be related to the increased cardiac output caused by chronic anaemia. Left ventricular performance is better preserved when chelation treatment is adjusted to maintain the serum ferritin concentration at < 1000 ng/ml.
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Disfunción Ventricular Izquierda/fisiopatología , Remodelación Ventricular/fisiología , Talasemia beta/fisiopatología , Adolescente , Adulto , Niño , Diástole , Ecocardiografía Doppler , Femenino , Humanos , Masculino , Contracción Miocárdica , Volumen Sistólico , Sístole , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/diagnóstico por imagen , Talasemia beta/sangreRESUMEN
A pathological hallmark of neurodegenerative tauopathies, including Alzheimer's disease and a group of clinically heterogeneous frontotemporal dementias, is the presence of intracellular neurofibrillary protein lesions (reviewed in Spillantini and Goedert, TINS 10 (1998) 428). The principal component of these structures is the microtubule-associated protein tau. Although tau is normally a highly soluble protein enriched in axons, in these deposits, it is abnormally hyperphosphorylated, insoluble, and redistributed to the somatodendritic compartments of neurons. Through ultrastructual analyses, it has been determined that the tau protein in these lesions is filamentous and organized into paired-helical filaments, straight filaments, or ribbon-like filaments (Goedert et al., The Molecular and Genetic Basis of Neurological Disease (1997) 613). By the dynamic binding of microtubules, tau is thought to promote the structural stability of axons, but whether tau aggregates contribute to neurodegeneration through a direct toxicity on normal cellular functions such as organelle transport or an indirect effect on microtubule stability, is currently unknown. The identification of mutations in the tau locus in patients with familial frontotemporal dementia and Parkinsonism linked to chromosome 17 has demonstrated that mutations in tau are sufficient to cause neurodegenerative disease (Poorkaj et al., Ann. Neurol. 43 (1998) 815; Hutton et al., Nature 393 (1998) 702). To elucidate the mechanisms by which tau dysfunction contributes to neuronal loss, we have sought to model human tauopathies in a genetically tractable organism. Here we describe the isolation of a Drosophila tau cDNA (GenBank accession number AY032977), the production of antibodies that recognize the encoded protein, and their use in determining the expression and subcellular localization of the fly tau protein.
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Proteínas de Drosophila/genética , Drosophila/embriología , Drosophila/genética , Genes de Insecto , Proteínas tau/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN Complementario/genética , Drosophila/crecimiento & desarrollo , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Regulación del Desarrollo de la Expresión Génica , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Humanos , Inmunohistoquímica , Hibridación in Situ , Datos de Secuencia Molecular , Mutación , Sistema Nervioso/embriología , Sistema Nervioso/crecimiento & desarrollo , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Proteínas tau/metabolismoAsunto(s)
Metabolismo de los Hidratos de Carbono , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de Drosophila , Proteínas de Transporte de Nucleótidos , Transporte de Proteínas/fisiología , Animales , Carbohidratos/química , Drosophila/genética , Genes de Insecto , Glicosilación , Proteoglicanos de Heparán Sulfato/biosíntesis , Proteínas de la Membrana/metabolismo , Modelos Biológicos , Nucleótidos/química , Nucleótidos/metabolismo , Receptores Notch , Transducción de Señal/fisiologíaRESUMEN
Presenilins are needed for proteolytic processing of transmembrane proteins of the Notch/Lin-12 family and for cleavage of the amyloid precursor protein. Accumulating evidence now strongly implicates Presenilin as the catalytic core of a multiprotein complex that executes an unusual intramembranous cleavage of its substrates. In the case of amyloid precursor protein, this cleavage contributes to the generation of small, toxic amyloid peptides that trigger the pathological development of Alzheimer's disease. In the Notch/Lin-12 pathway, Presenilin-mediated cleavage of the receptor is a crucial feature of ligand-induced receptor activation and signal transduction. In this pathway, the Presenilins perform a regulated cleavage event that follows additional processing steps during receptor maturation and ligand-induced ectodomain removal.
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Proteínas de Caenorhabditis elegans , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/fisiología , Receptores de Superficie Celular , Factores de Transcripción , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Proteínas del Helminto/metabolismo , Proteínas del Helminto/fisiología , Humanos , Modelos Biológicos , Presenilina-1 , Presenilina-2 , Receptor Notch1 , Receptores Notch , Transducción de SeñalRESUMEN
Gonadotrophin-releasing hormone agonists (GnRHa) have been demonstrated as the therapy of choice for central precocious puberty (CPP). Few studies have provided male patients' adult height data. In our multicenter study we evaluated long-term effects of different GnRHa preparations and final/near-final height (FH) in 12 boys with CPP and analyzed the factors influencing FH. Patients' mean chronological age at the time of diagnosis was 7.6 +/- 0.9 yr. Three patients were treated only with triptorelin at a mean dose of 90 microg/kg i.m. every 28 days. Nine patients initially received buserelin (at a mean initial dose of 53.4 microg/kg/day i.n. divided into 3-6 equal doses) or buserelin (at a mean dose of 36.7 microg/kg/day s.c.) and were subsequently switched to triptorelin. The GnRHa therapy was continued for 4.1 +/- 0.6 yr (range 2.9-5.4). The mean predicted adult height increased from 169.9 +/- 4.2 cm at diagnosis to 180.7 +/- 6.0 cm at the end of treatment. Mean FH was 176.1 +/- 6.1 cm (170.1-190.7), corresponding to mean SDS(CA) 0.4 +/- 0.8 (-0.6/2.5), mean SDSBA 0.2 +/- 0.9 (-0.6/2.4) and mean corrected SDS for target height of 0.4 +/- 0.6 (-0.8/1.2). Multiple regression analysis revealed that FH was mainly influenced by target height and height at discontinuation of GnRHa therapy. The present data indicate that GnRHa therapy significantly improves growth prognosis in boys with CPP and fully restores genetic height potential.
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Estatura/efectos de los fármacos , Encefalopatías/complicaciones , Hormona Liberadora de Gonadotropina/agonistas , Pubertad Precoz/tratamiento farmacológico , Pubertad Precoz/etiología , Desarrollo Óseo , Niño , Femenino , Humanos , Masculino , Pronóstico , Pubertad Precoz/patología , Pubertad Precoz/fisiopatologíaAsunto(s)
Carbohidratos/fisiología , Drosophila/embriología , Proteínas de Insectos/fisiología , Proteínas de la Membrana/fisiología , Animales , Proteínas de Drosophila , Desarrollo Embrionario y Fetal/fisiología , Glicosilación , Humanos , Ligandos , Mamíferos/embriología , N-Acetilglucosaminiltransferasas/fisiología , Unión Proteica , Receptores de Superficie Celular/fisiología , Receptores Notch , Transducción de SeñalRESUMEN
Regulated proteolysis is a critical feature of many intercellular signalling pathways that control cell-fate specification and tissue patterning during metazoan development. The roles of proteolysis in three different pathways, the Toll, Hedgehog, and Notch pathways, are described to illustrate the importance of specific protein cleavages in both extracellular ligand-receptor interactions and intracellular signal transduction. An emerging principle is the use of proteolysis to control the maturation and activation of receptors, to limit the spatial diffusion of their ligands, and to modulate the subcellular localization or transcriptional activity of DNA-binding factors in response to receptor-ligand interactions at the cell surface.
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Tipificación del Cuerpo , Desarrollo Embrionario , Desarrollo Embrionario y Fetal , Proteínas/metabolismo , Transducción de Señal , Animales , Drosophila/fisiología , Endopeptidasas/metabolismo , Humanos , Proteínas de Insectos/metabolismo , Fragmentos de Péptidos/metabolismoRESUMEN
The ability of Drosophila genetics to reveal new insights into human neurodegenerative disease is highlighted not only by mutants in flies that show neuronal cell loss, but also by targeted expression of human disease genes in the fly. Moreover, study of Drosophila homologs of various human disease genes provides new insight into fundamental aspects of protein function. These recent findings confirm the remarkable homology of gene function in flies when compared with humans. With the advent of complete genomic sequencing on the horizon, Drosophila will continue to be an outstanding model system in which to unravel the complexities, causes and treatments for human neural degeneration.
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Modelos Genéticos , Enfermedades Neurodegenerativas/genética , Animales , Modelos Animales de Enfermedad , Drosophila/genética , Humanos , MutagénesisRESUMEN
A comparative analysis of the genomes of Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae-and the proteins they are predicted to encode-was undertaken in the context of cellular, developmental, and evolutionary processes. The nonredundant protein sets of flies and worms are similar in size and are only twice that of yeast, but different gene families are expanded in each genome, and the multidomain proteins and signaling pathways of the fly and worm are far more complex than those of yeast. The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.
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Caenorhabditis elegans/genética , Drosophila melanogaster/genética , Genoma , Proteoma , Saccharomyces cerevisiae/genética , Animales , Apoptosis/genética , Evolución Biológica , Caenorhabditis elegans/química , Caenorhabditis elegans/fisiología , Adhesión Celular/genética , Ciclo Celular/genética , Drosophila melanogaster/química , Drosophila melanogaster/fisiología , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Genes Duplicados , Enfermedades Genéticas Congénitas/genética , Genética Médica , Proteínas del Helminto/química , Proteínas del Helminto/genética , Humanos , Inmunidad/genética , Proteínas de Insectos/química , Proteínas de Insectos/genética , Familia de Multigenes , Neoplasias/genética , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/fisiología , Transducción de Señal/genéticaRESUMEN
OBJECTIVE: To investigate if markers of exposure to foodborne and orofecal microbes versus airborne viruses are associated with atopy and respiratory allergies. DESIGN: Retrospective case-control study. PARTICIPANTS: 240 atopic cases and 240 non-atopic controls from a population sample of 1659 participants, all Italian male cadets aged 17-24. SETTING: Air force school in Caserta, Italy. MAIN OUTCOME MEASURES: Serology for Toxoplasma gondii, Helicobacter pylori, hepatitis A virus, measles, mumps, rubella, chickenpox, cytomegalovirus, and herpes simplex virus type 1; skin sensitisation and IgE antibodies to relevant airborne allergens; total IgE concentration; and diagnosis of allergic asthma or rhinitis. RESULTS: Compared with controls there was a lower prevalence of T gondii (26% v 18%, P=0.027), hepatitis A virus (30% v 16%, P=0.004), and H pylori (18% v 15%, P=0.325) in atopic participants. Adjusted odds ratios of atopy decreased with a gradient of exposure to H pylori, T gondii, and hepatitis A virus (none, odds ratio 1; one, 0. 70; two or three, 0.37; P for trend=0.000045) but not with cumulative exposure to the other viruses. Conversely, total IgE concentration was not independently associated with any infection. Allergic asthma was rare (1/245, 0.4%) and allergic rhinitis infrequent (16/245, 7%) among the participants (245/1659) exposed to at least two orofecal and foodborne infections (H pylori, T gondii, hepatitis A virus). CONCLUSION: Respiratory allergy is less frequent in people heavily exposed to orofecal and foodborne microbes. Hygiene and a westernised, semisterile diet may facilitate atopy by influencing the overall pattern of commensals and pathogens that stimulate the gut associated lymphoid tissue thus contributing to the epidemic of allergic asthma and rhinitis in developed countries.
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Microbiología del Aire , Asma/microbiología , Heces/microbiología , Microbiología de Alimentos , Boca/microbiología , Hipersensibilidad Respiratoria/microbiología , Adolescente , Adulto , Animales , Asma/epidemiología , Asma/parasitología , Estudios de Casos y Controles , Heces/parasitología , Humanos , Higiene , Inmunoglobulina E/análisis , Italia/epidemiología , Masculino , Boca/parasitología , Hipersensibilidad Respiratoria/epidemiología , Hipersensibilidad Respiratoria/parasitología , Estudios Retrospectivos , ToxoplasmaAsunto(s)
Enfermedad de Alzheimer/metabolismo , Fibrinolisina/fisiología , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Humanos , Modelos Biológicos , Plasminógeno/metabolismo , Estructura Terciaria de Proteína , Activador de Tejido Plasminógeno/química , Activador de Tejido Plasminógeno/metabolismo , Regulación hacia ArribaRESUMEN
Normal differentiation requires an appropriately orchestrated sequence of developmental events. Regulation of cell survival and cell death is integrated with these events to achieve proper cell number, cell type, and tissue structure. Here we review regulation of cell survival in the context of a precisely patterned neural structure: the Drosophila compound eye. Numerous mutations lead to altered differentiation and are frequently accompanied by altered patterns of cell death. We discuss various critical times of normal eye development, highlighting how inappropriate regulation of cell death contributes to different mutant phenotypes associated with genes that specify the entire eye primordia, others that pattern the retina, and those that eliminate extraneous cells to refine the precise pigment cell lattice. Finally, we address how the Drosophila eye may allow identification of additional mechanisms that contribute to the normal integration of cell survival with appropriate events of cellular differentiation.
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Drosophila/embriología , Drosophila/crecimiento & desarrollo , Ojo/embriología , Ojo/crecimiento & desarrollo , Neuronas/fisiología , Animales , Muerte Celular , Diferenciación Celular , Drosophila/genética , MorfogénesisRESUMEN
We performed a systematic lethal mutagenesis of the genomic region uncovered by Df(3L)rdgC-co2 (cytological interval 77A-D) to isolate mutations in the single known Presenilin (Psn) gene of Drosophila melanogaster. Because this segment of chromosome III has not been systematically characterized before, inter se complementation testing of newly recovered mutants was carried out. A total of 79 lethal mutations were isolated, representing at least 17 lethal complementation groups, including one corresponding to the Psn gene. Fine structure mapping of the genomic region surrounding the Psn transcription unit by transgenic rescue experiments allowed us to localize two of the essential loci together with Psn within an approximately 12-kb genomic DNA region. One of these loci, located 3' to Psn, encodes a Drosophila protein related to the yeast 60S ribosomal protein L10 precursor. We also determined which of the newly recovered lethal mutant groups correspond to previously isolated lethal P-element insertions, lethal inversion breakpoints, and lethal polo gene mutants. Point mutations were identified in all five recovered Psn alleles, one of which results in a single amino acid substitution G-E at a conserved residue in the C-terminal cytoplasmic tail of the protein, suggesting an important functional role for this C-terminal domain of Presenilin. In addition, some viable mutations were recovered in the screen, including new alleles of the clipped and inturned loci.
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Proteínas de Drosophila , Drosophila melanogaster/genética , Proteínas de la Membrana/genética , Animales , Secuencia de Bases , Clonación Molecular , Cartilla de ADN , Drosophila melanogaster/ultraestructura , Genes Letales , Prueba de Complementación Genética , Microscopía Electrónica de Rastreo , Mutación , PresenilinasRESUMEN
Maintaining high Ca(2+) concentrations in the lumen of the endoplasmic reticulum is important for protein synthesis and transport. We identified a lethal complementation group recovered in a screen for mutations that reduce Notch activity as loss-of-function alleles of the Drosophila Ca(2+)-ATPase gene Ca-P60A. Analysis of Ca-P60A mutants indicates that Ca(2+)-ATPase is essential for cell viability and tissue morphogenesis during development. Cultured cells treated with Ca(2+)-ATPase inhibitors exhibit impaired Notch cleavage and receptor trafficking to the cell surface, explaining the genetic interaction between Ca(2+)-ATPase and Notch. Notch and several other transmembrane proteins are mislocalized in tissue clones homozygous for Ca-P60A mutations, demonstrating a general effect on membrane protein trafficking caused by a deficiency in Ca(2+)-ATPase.
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ATPasas Transportadoras de Calcio/metabolismo , Drosophila/enzimología , Proteínas de la Membrana/metabolismo , Animales , Línea Celular , Enfermedad de Darier/genética , Drosophila/genética , Proteínas de Drosophila , Inhibidores Enzimáticos/farmacología , Genes de Insecto , Genes Letales , Humanos , Inmunohistoquímica , Indoles/farmacología , Microscopía Electrónica de Rastreo , Mutación , Fenotipo , Receptores de Superficie Celular/metabolismo , Receptores Notch , Transducción de Señal , Tapsigargina/farmacología , TransfecciónRESUMEN
The Drosophila fat facets gene encodes a deubiquitinating enzyme required during eye development to limit the number of photoreceptors in each facet to eight. Ubiquitin is a small polypeptide that targets proteins for degradation by the proteasome. Deubiquitinating enzymes cleave ubiquitin-protein bonds. In order to investigate the role of FAT FACETS in the ubiquitin pathway, genetic interactions between fat facets and the Drosophila UbcD1 gene were assessed. In addition, three yeast deubiquitinating enzyme genes were tested for their ability to substitute for fat facets in the developing Drosophila eye and for their effects on eye morphology. The results of these experiments support the hypothesis that FAT FACETS activity antagonizes that of the proteolytic machinery. The implications of these results for the specificity of FAF and yeast UBPs are discussed as well.