424 research outputs found
Fons illimis theologiae scoticae marianae e paradiso virgineo latices suos ubertim effundens ... : tomus primus, duos continens tractatus, de essentia & attributis maternitatis unum, de mirabili praedestinatione deiparae alterum
No full textSign.: [calderón]-2[calderón], A-Z, 2A-2V, 2X, 2Y, 2ZPort. con orla tipA f,. de grav. é cal
Laboratory testing of individuals with severe alpha1-antitrypsin deficiency in three European centres.
No full textalpha(1)-Antitrypsin (AT) deficiency is a hereditary disorder that may lead to early-onset emphysema, and chronic liver disease later in life. Although there are validated methods for testing, the vast majority of alpha(1)-AT-deficient individuals remain undiagnosed. Recommendations have been published for the testing and diagnosis of alpha( 1)-AT deficiency; however, guidelines on best practice are not well established. In our article, we review the developments in diagnostic techniques that have taken place in recent years, and describe the practices used in our three European centres. The determination of the level of alpha(1)-AT and genotyping are reported as the main diagnostic steps, whereas isoelectric focusing (also referred to as phenotyping) is reserved for confirmatory analysis. The following recommendations for best practice are put forward: detection of all PiZZ and other severe deficiency individuals; automated genotyping; preparation of reference standards; quality control programmes; development of standard operating procedure documents; and standardised methods for the collection of dried blood samples. Closer cooperation between laboratories and the sharing of knowledge are recommended, with the objectives of improving the efficiency of the diagnosis of severe alpha(1)-AT deficiency, increasing the numbers of individuals who are detected with the disorder, and assisting the establishment of new patient identification programmes
Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial
No full textBackground: Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors. Methods: In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA1c) of 7·0–10·5%, body-mass index of at least 25 kg/m2, stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA1c, and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete. Findings: Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA1c of 8·17% (SD 0·91), the reductions in HbA1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from –0·59% to –1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%–93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (–7·5 kg to –12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from –9·8 kg to –15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. A higher incidence of nausea (12–24%), diarrhoea (15–17%), decreased appetite (6–12%), and vomiting (6–10%) was reported in participants treated with tirzepatide than in those treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia (<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment. Interpretation: In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists. Funding: Eli Lilly and Company
Macrocyclic Pyclen-Based Gd3+ Complex with High Relaxivity and pH Response
No full textWe report the synthesis and characterization of the macrocyclic ligand 2,2′-((2-(3,9-bis(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-6-yl)ethyl)azanediyl)diacetic acid (H4L) and several of its complexes with lanthanide ions. The structure of the free ligand was determined using X-ray diffraction measurements. Two N atoms of the pyclen moiety in the trans position are protonated in the solid state, together with the exocyclic N atom and one of the carboxylate groups of the ligand. The relaxivity of the Gd3+ complex was found to increase from 6.7 mM-1 s-1 at pH 8.6 to 8.5 mM-1 s-1 below pH ≈ 6.0. Luminescence lifetime measurements recorded from H2O and D2O solutions of the Eu3+ complex evidence the presence of a single complex species in solution at low pH (a5.0) that contains two inner-sphere water molecules. DFT calculations suggest that the coordination environment of the Ln3+ ion is fulfilled by the four N atoms of the pyclen unit, two oxygen atoms of the macrocyclic acetate groups, and an oxygen atom of an exocyclic carboxylate group. The two inner-sphere water molecules complete coordination number nine around the metal ion. At high pH (a9.3), the lifetime of the excited 5D0 level of Eu3+ displays a biexponential behavior that can be attributed to the presence of two species in solution with hydration numbers of q = 0 and q = 1. The 1H NMR and DOSY spectra recorded from solutions of the Eu3+ and Y3+ complexes reveal a structural change triggered by pH and the formation of small aggregates at high pH values
Association between circulating alpha-1 antitrypsin polymers and lung and liver disease
Get PDFBackground: Alpha-1 antitrypsin deficiency (AATD) is considered one of the most common genetic diseases and is characterised by the misfolding and polymerisation of the alpha-1 antitrypsin (AAT) protein within hepatocytes. The relevance of circulating polymers (CP) of AAT in the pathogenesis of lung and liver disease is not completely understood. Therefore, the main objective of our study was to determine whether there is an association between the levels of CP of AAT and the severity of lung and liver disease. Method: This was a cross-sectional study in patients with different phenotypes of AATD and controls. To quantify CP, a sandwich ELISA was performed using the 2C1 monoclonal antibody against AAT polymers. Sociodemographic data, clinical characteristics, and liver and lung parameters were collected. Results: A cohort of 70 patients was recruited: 32 Pi*ZZ (11 on augmentation therapy); 29 Z-heterozygous; 9 with other genotypes. CP were compared with a control group of 47 individuals (35 Pi*MM and 12 Pi*MS). ZZ patients had the highest concentrations of CP (p < 0.001) followed by Z heterozygous. The control group and patients with Pi*SS and Pi*SI had the lowest CP concentrations. Pi*ZZ also had higher levels of liver stiffness measurements (LSM) than the remaining AATD patients. Among patients with one or two Z alleles, two patients with lung and liver impairment showed the highest concentrations of CP (47.5 μg/mL), followed by those with only liver abnormality (n = 6, CP = 34 μg/mL), only lung (n = 18, CP = 26.5 μg/mL) and no abnormalities (n = 23, CP = 14.3 μg/mL). Differences were highly significant (p = 0.004). Conclusions: Non-augmented Pi*ZZ and Z-patients with impaired lung function and increased liver stiffness presented higher levels of CP than other clinical phenotypes. Therefore, CP may help to identify patients more at risk of developing lung and liver disease and may provide some insight into the mechanisms of disease
Rhagoletis nicaraguensis Hernandez-Ortiz & Frias 2000
No full textRhagoletis nicaraguensis Hernández-Ortiz & Frías Rhagoletis nicaraguensis Hernández-Ortiz & Frías 2000: 17 (Holotype ♀ (Instituto de Ecología, Xalapa), Nicaragua: Meseta de los Pueblos, Carazo, San Marcos, 1 Oct 1994, M. Niklaus-Ruiz). Distribution. This species has been recorded from Nicaragua (Hernández-Ortiz & Frías 2000); additional specimens from Costa Rica are reported here. Specimens examined. COSTA RICA: Cartago: Tres Ríos, [9.90000°N 83.98333°W], 21 May 1988, C. Centeno, 1♂ (UCRSJ). San José: San Antonio de Escazú, [9.91667°N 84.13333°W], 1300 m, Jun 1989, W. Eberhard, 1♀ (UCRSJ); San Antonio de Escazú, [9.91667°N 84.13333°W], 1300 m, Sep 1992, W. Eberhard, 1♀ (USNM USNMENT00214381); Ciudad Universitaria [Rodrigo Facio], [9.93583°N 84.05056°W], 7 Jul 1978, L. F. Jirón, 1♀ paratype R. jamaicensis (USNM USNMENT01355413); Santa Ana, [9.93199°N 84.17598°W], AAT traps, 14 May 1958, E. Morales, 3♀ (USNM USNMENT01355410–12). Biology. Host plant unknown. Comments. Hernández-Ortiz & Frías (2000) distinguished R. jamaicensis from R. nicaraguensis on the basis of whether the discal and subapical bands were connected posteriorly (connected in R. nicaraguensis, separated in R. jamaicensis), the breadth of the connection between the subapical and posterior apical bands (hyaline area between them not entering cell r 4+ 5 in R. nicaraguensis), and the width of the brown basal area on the disk of the scutellum (narrower in R. nicaraguensis). Martínez et al. (2017) described the variation in these characters in Colombian populations of R. jamaicensis, particularly the wing characters, and they likewise vary in the newly reported specimens from Colombia. The examined specimens from Costa Rica vary in the connection of the discal and subapical bands. Although they have the posterior apical band more narrowly connected to the subapical band and vary slightly in the width of the basal brown area on the scutellum, the latter area is narrow. These specimens are therefore tentatively considered to be R. nicaraguensis rather than R. jamaicensis. Further study of these species is needed to confirm their status.Published as part of Rodriguez, Pedro Alexander, Norrbom, Allen L., Peñaranda, Guadalupe Caicedo Emilio Arévalo & Balseiro, Francisco, 2021, New species and host plant records for Neotropical Rhagoletis Loew (Diptera: Tephritidae), pp. 231-244 in Zootaxa 5060 (2) on pages 239-240, DOI: 10.11646/zootaxa.5060.2.4, http://zenodo.org/record/562725
Lifestyle Factors Associated with Children’s and Adolescents’ Adherence to the Mediterranean Diet Living in Mediterranean Countries: The DELICIOUS Project
No full textBackground/Objectives. Traditional dietary patterns are being abandoned in Mediterranean countries, especially among younger generations. This study aimed to investigate the potential lifestyle determinants that can increase adherence to the Mediterranean diet in children and adolescents. Methods. This study is a cross-sectional analysis of data from five Mediterranean countries (Italy, Spain, Portugal, Egypt, and Lebanon) within the context of the EU-funded project DELICIOUS (UnDErstanding consumer food choices & promotion of healthy and sustainable Mediterranean Diet and LIfestyle in Children and adolescents through behavIOUral change actionS). This study comprised information on 2011 children and adolescents aged 6–17 years old collected during 2023. The main background characteristics of both children and parents, including age, sex, education, and family situation, were collected. Children’s eating (i.e., breakfast, place of eating, etc.) and lifestyle habits (i.e., physical activity level, sleep, and screen time) were also investigated. The level of adherence to the Mediterranean diet was assessed using the KIDMED index. Logistic regression analyses were performed to test for likelihood of higher adherence to the Mediterranean diet. Results. Major determinants of higher adherence to the Mediterranean diet were younger age, higher physical activity level, adequate sleep duration, and, among dietary habits, having breakfast and eating with family members and at school. Parents’ younger age and higher education were also determinants of higher adherence. Multivariate adjusted analyses showed that an overall healthier lifestyle and parents’ education were the factors independently associated with higher adherence to the Mediterranean diet. Conclusions. Higher adherence to the Mediterranean diet in children and adolescents living in the Mediterranean area is part of an overall healthy lifestyle possibly depending on parents’ cultural background
Pure partial trisomy of 6p12.1-p22.1 secondary to a familial 12/6 insertion in two malformed babies
No full textWe describe two malformed infants with trisomy 6p12.1ep22.1 due to 12/6 interchromosomal insertion.
The phenotypic data observed in these patients are compared chiefly with a case cytogenetically similar
described by Villa et al. [A. Villa, E.G. Gomez, L. Rodriguez, R.H. Rastrollo, M.E. Martinez Tallo,
M.L. Martinez-Frias, Interstitial tandem duplication of 6p: a case with partial trisomy (6)(p12p21.3), Am.
J. Med. Genet. 90 (2000) 369e375]. All three infants are trisomic for a genomic segment which largely
overlaps that reported as duplicated in previous cases, but with the addition of a more proximal segment,
extending from 6p12 to 6p21. We suggest that some of their phenotypic anomalies are due to the trisomy
of this chromosomal region. We also speculate on the possible role played by the TFAP2B (Transcription
Factor AP2-beta) gene, which is one of the genes mapped on the duplicated segment
Whole-genome characterization and resistance-associated substitutions in a new HCV genotype 1 subtype
No full textGeorg von Massow,1 Damir Garcia-Cehic,1,2 Josep Gregori,1–3 Francisco Rodriguez-Frias,2,4 María Dolores Macià,5 Ana Escarda,6 Juan Ignacio Esteban,1–2,7 Josep Quer1–2,71Liver Unit, Liver Diseases – Viral Hepatitis, Vall d’Hebron Institut of Research (VHIR) – Hospital Universitari Vall d’Hebron (HUVH), Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; 3Roche Diagnostics S.L., Sant Cugat del Vallès, Barcelona, Spain; 4Biochemistry and Microbiology Department, VHIR-HUVH, Barcelona, Spain; 5Unidad de Microbiología Molecular, Servicio de Microbiología, Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), Hospital Universitario Son Espases, Mallorca, Spain; 6Digestive Department, Hospital Universitario Son Espases, Mallorca, Spain; 7Medicine Department, Universitat Autònoma de Barcelona, Barcelona, SpainAbstract: Hepatitis C virus (HCV) is a highly variable infectious agent, classified into 8 genotypes and 86 subtypes. Our laboratory has implemented an in-house developed high-resolution HCV subtyping method based on next-generation sequencing (NGS) for error-free classification of the virus using phylogenetic analysis and analysis of genetic distances in sequences from patient samples compared to reference sequences. During routine diagnostic, a sample from an Equatorial Guinea patient could not be classified into any of the existing subtypes. The whole genome was analyzed to confirm that the new isolate could be classified as a new HCV subtype. In addition, naturally occurring resistance-associated substitutions (RAS) were analyzed by NGS. Whole-genome analysis based on p-distances suggests that the sample belongs to a new HCV genotype 1 subtype. Several RAS in the NS3 (S122T, D168E and I170V) and NS5A protein (Q(1b)24K, R(1b)30Q and Y93L+Y93F) were found, which could limit the use of some inhibitors for treating this subtype. RAS studies of new subtypes are of great interest for tailoring treatment, as no data on treatment efficacy are reported. In our case, the patient has not yet been treated, and the RAS report will be used to design the most effective treatment.Keywords: subtype, direct-acting antivirals, HCV, genotype
Por Don Gregorio de el Hierro Fernandez de Mançanos, y Doña Iuana Thomasa de Oteo Angulo, su legitima muger ... con Diego Fernández Mançanos ... vezino de Frias sobre reivindicacion de diferentes bienes ...
No full textTexto firmado por el Lic. D. Geronimo Fierro Rodriguez CoboPrecede al tit. 'Jesús, Maria, Joseph'Fecha tomada del texto, 1697Sign.: A-F\p2\s, G\p1\sTexto con reclamosEnc. perg. con correillas, cortes salpicadosEnc. junto con otras obras formando un vol. factici
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