IntroductionSleep problems are a growing public health concern being related, among others, to an increased risk of cardiovascular diseases or worse cognitive functioning. In addition, they can ...affect aspects related to personal motivation and quality of life. However, very few studies have analysed the possible determinants of sleep quality in the adult population as a whole, establishing patterns based on these determinants.The objectives are to evaluate the determinants of sleep quality in a representative sample of the general adult population between 25 and 65 years old, and to establish patterns of sleep quality based on lifestyles, psychological factors, morbidities, sociodemographic variables, biological markers and other possible determinants.Methods and analysisDescriptive observational cross-sectional study. The study population will include a representative sample of 500 people between 25 and 65 years old from the cities of Salamanca and Ávila (Spain) selected by random sampling stratified by age groups and sex. A 90-minute visit will be performed, during which sleep quality will be assessed. The variables collected will be: morbidity, lifestyles (physical activity, diet, toxic habits), psychological factors (depression, stress, occupational stress and anxiety), socioeconomic and work-related variables, habitability conditions of the habitual residence and rest area, screen time, relaxation techniques and melatonin as a biological marker related to sleep quality.DiscussionWith the results of this work, improved interventions for behaviour modification could be designed, as well as intervention and education programmes or other research aimed at improving sleep quality.Ethics and disseminationThis study has a favourable opinion from the Ethics Committee for Drug Research of the Health Areas of Salamanca and Ávila (CEim Code: PI 2021 07 815). The results of this study will be published in international impact journals of different specialties.Trial registration numberNCT05324267.
The expression of CD33, a restricted leukocyte antigen considered specific for myeloid lineage, has been studied extensively on lymphoid cells. We demonstrated that wide subsets of mitogen- or ...alloantigen-activated human T and natural killer (NK) cells express CD33 at protein and nucleic acid levels. CD33+ and CD33- T and NK cell populations showed identical surface expression of activation markers such as CD25, CD28, CD38, CD45RO, or CD95. Myeloid and lymphoid CD33 cDNA were identical. However, lymphoid CD33 protein had lower molecular weight, suggesting cell type-specific, post-translational modifications. Additionally, reverse transcriptase-polymerase chain reaction and Northern blot analysis showed an unknown CD33 isoform (CD33m) expressed on all CD33+ cell lines or T cell clones tested. CD33m was identical to CD33 (CD33M) in the signal peptide, the immunoglobulin (Ig) domain C2, the transmembrane, and the cytoplasmic regions but lacked the extracellular ligand-binding variable Ig-like domain encoded by the second exon. CD33m mRNA was mostly detected on NKL and myeloid cell lines but poorly expressed on B cell lines and T lymphocytes. The CD33m extracellular portion was successfully expressed as a soluble fusion protein on transfected human cells, suggesting a functional role on cell membranes. Cross-linking of CD33 diminished the cytotoxic activity of NKL cells against K562 and P815 target cells, working as an inhibitory receptor on NK cells. These data demonstrate that CD33 expression is not restricted to the myeloid lineage and could exist as two different splicing variants, which could play an important role in the regulation of human lymphoid and myeloid cells.
Background
Alcoholic cirrhosis (AC) is a common cause of death among individuals abusing alcohol. In the last resort, liver transplantation (LT) is considered the only solution to save the patient's ...life, generating socioeconomic and public health problems. Clinical and sociodemographic characteristics, rejection frequency, and short‐ and long‐term graft survival are not well known in end‐term AC patients undergoing LT. The aim was to determine the sociodemographic and clinical characteristics, their incidence in LT, main pre‐ and posttransplant complications, and short‐ and long‐term post‐transplant graft survival in AC patients in southeastern Spain.
Methods
The medical records of 1,026 patients who underwent LT over the last 23 years were retrospectively reviewed, and demographic data and posttransplant survivals were analyzed and compared. Biochemical characteristics, major pre‐ and posttransplant complications and short‐ and long‐term survivals were analyzed in a total of 398 male patients with AC undergoing LT.
Results
AC and viral cirrhosis are the main indications for LT in our study. Mostly represented in our study are AC men without associated viral infections with a mean age of 53.06 years. Main pretransplant complications in AC patients are ascites (78.3%) and encephalopathy (43.5%), while acute graft rejection is the most common liver posttransplant complication (26.6%), nevertheless with low graft loss frequency (1.1%). AC and autoimmune cirrhosis show the best posttransplant survival in both the short and long term. Patients with AC included on the waiting list for LT were Child‐Pugh class B (52.1%) and Model for End‐Stage Liver Disease score of 10 to 19 (71.2%). The highest percentage of AC patient survival was observed at 1 year posttransplant (81.2%) and progressively decreased over time up to 10 years posttransplant (69.6%). Pretransplant complications such as ascites and encephalopathy did not have an influence on the percentage of posttransplant survivals, although better survival rates were observed in nonviral AC patients.
Conclusions
AC without viral infections is the main indication for LT in southeastern Spain although its frequency has decreased in last decade. AC is a good indication for LT for its high survival rate and few posttransplant complications. Despite having a high percentage of pretransplant complications (ascites and encephalopathy) but does not appear to influence survivals being observed posttransplant survival rates above those expected. Conversely, viral infections in the patient with AC decrease patient survivals. The main future goals are design new strategies to detect, treat, and reduce AC frequency in our population and know alcoholic recidivism rate posttransplant in our population.
This figure shows Kaplan–Meier patient's survival curves according to the main indications for liver transplant in south‐eastern Spain in the short‐ and long‐term over 10 years. A comparative table showing statistically significant differences between the survival of alcoholic cirrhosis patients (with and without associated viral infections) and other liver transplant indications is also shown: total number of patients included in each group considered; NS, not significant.
We report the peculiar chemical abundance patterns of 11 atypical Milky Way (MW) field red giant stars observed by the Apache Point Observatory Galactic Evolution Experiment (APOGEE). These atypical ...giants exhibit strong Al and N enhancements accompanied by C and Mg depletions, strikingly similar to those observed in the so-called second-generation (SG) stars of globular clusters (GCs). Remarkably, we find low Mg abundances (Mg/Fe < 0.0) together with strong Al and N overabundances in the majority (5/7) of the metal-rich (Fe/H −1.0) sample stars, which is at odds with actual observations of SG stars in Galactic GCs of similar metallicities. This chemical pattern is unique and unprecedented among MW stars, posing urgent questions about its origin. These atypical stars could be former SG stars of dissolved GCs formed with intrinsically lower abundances of Mg and enriched Al (subsequently self-polluted by massive AGB stars) or the result of exotic binary systems. We speculate that the stars Mg-deficiency as well as the orbital properties suggest that they could have an extragalactic origin. This discovery should guide future dedicated spectroscopic searches of atypical stellar chemical patterns in our Galaxy, a fundamental step forward to understanding the Galactic formation and evolution.
ABSTRACT
Immunological molecules are implicated in inflammatory disorders, including inflammatory bowel disease (IBD; Crohn disease CD and ulcerative colitis UC). Killer cell immunoglobulin‐like ...receptors (KIRs) are also genetically variable proteins involved in immune function. They are expressed by NK cells and certain T lymphocytes, regulate specificity and function by interaction with HLA Class I molecules, may be either inhibitory or activating and are polymorphic both in terms of alleles and haplotype gene content. Genetic associations between activating KIRs and certain autoimmune and inflammatory diseases have been reported; however, a possible association between KIR and IBD remains unclear. The aim of this study was to determine the relationship between KIR repertoire and IBD pathologies in a Spanish cohort. KIR variability was analyzed using PCR–sequence specific oligonucleotide probes (SSOP). Inhibitory KIR2DL5 was found more frequently in UC and IBD patient groups than in healthy controls (P = 0.028 and P = 0.01, respectively), as was activating KIR2DS1 (P = 0.02, Pc > 0.05, UC vs. Controls; P = 0.001, Pc = 0.01, IBD vs Controls; P = 0.01, Pc > 0.05, Controls vs CR), KIR2DS5 (P = 0.0028, Pc = 0.04, Controls vs UC; P = 0.0001, Pc = 0.0017, Controls vs IBD; P = 0.01, Pc > 0.05, Controls vs CD) and KIR3DS1 (P = 0.012, Pc > 0.05, Controls vs IBD). Our data suggest that imbalance between activating and inhibitory KIR may partially explain the different pathogeneses of these IBDs and that there is a hypothetical role for the telomeric B region (which contains both KIR2DS5 and KIR2DS1) in these diseases.
•Imipenem/relebactam and ceftazidime/avibactam resistance was evaluated in K. pneumoniae.•Resistance to imipenem/relebactam and ceftazidime/avibactam develops rapidly in all ...clones.•Imipenem/relebactam resistance involves OmpK36 disruption and KPC modification.•KPC variants selected with imipenem/relebactam show resistance to relebactam inhibition.•Development of imipenem/relebactam resistance imposes high fitness costs.
In order to inform and anticipate potential strategies aimed at combating KPC-producing Klebsiella pneumoniae infections, we analysed imipenem/relebactam and ceftazidime/avibactam single-step mutant frequencies, resistance development trajectories, differentially selected resistance mechanisms and their associated fitness cost using four representative high-risk K. pneumoniae clones.
Mutant frequencies and mutant preventive concentrations were determined using agar plates containing incremental concentrations of β-lactam/β-lactamase inhibitor. Resistance dynamics were determined through incubation for 7 days in 10 mL MH tubes containing incremental concentrations of each antibiotic combination up to their 64 × baseline MIC. Two colonies per strain from each experiment were characterized by antimicrobial susceptibility testing, whole genome sequencing and competitive growth assays (to determine in vitro fitness). KPC variants associated with imipenem/relebactam resistance were characterized by cloning and biochemical experiments, atomic models and molecular dynamics simulation studies.
Imipenem/relebactam prevented the emergence of single-step resistance mutants at lower concentrations than ceftazidime/avibactam. In three of the four strains evaluated, imipenem/relebactam resistance development emerged more rapidly, and in the ST512/KPC-3 clone reached higher levels compared to baseline MICs than for ceftazidime/avibactam. Lineages evolved in the presence of ceftazidime/avibactam showed KPC substitutions associated with high-level ceftazidime/avibactam resistance, increased imipenem/relebactam susceptibility and low fitness costs. Lineages that evolved in the presence of imipenem/relebactam showed OmpK36 disruption, KPC modifications (S106L, N132S, L167R) and strain-specific substitutions associated with imipenem/relebactam resistance and high fitness costs. Imipenem/relebactam-selected KPC derivatives demonstrated enhanced relebactam resistance through important changes affecting relebactam recognition and positioning.
Our findings anticipate potential resistance mechanisms affecting imipenem/relebactam during treatment of KPC-producing K. pneumoniae infections.
(NT3), through activation of its tropomyosin-related kinase receptor C (TrkC), modulates neuronal survival and neural stem cell differentiation. It is widely distributed in peripheral tissues ...(especially vessels and pancreas) and this ubiquitous pattern suggests a role for NT3, outside the nervous system and related to metabolic functions. The presence of the NT3/TrkC pathway in the adipose tissue (AT) has never been investigated. Present work studies in human and murine adipose tissue (AT) the presence of elements of the NT3/TrkC pathway and its role on lipolysis and adipocyte differentiation. qRT-PCR and immunoblot indicate that NT3 (encoded by
) was present in human retroperitoneal AT and decreases with age. NT3 was also present in rat isolated adipocytes and retroperitoneal, interscapular, perivascular, and perirenal AT. Histological analysis evidences that NT3 was mainly present in vessels irrigating AT close associated to sympathetic fibers. Similar mRNA levels of TrkC (encoded by
) and β-adrenoceptors were found in all ATs assayed and in isolated adipocytes. NT3, through TrkC activation, exert a mild effect in lipolysis. Addition of NT3 during the differentiation process of human pre-adipocytes resulted in smaller adipocytes and increased uncoupling protein-1 (UCP-1) without changes in β-adrenoceptors. Similarly, transgenic mice with reduced expression of NT3 (Ntf3 knock-in lacZ reporter mice) or lacking endothelial NT3 expression (Ntf3flox1/flox2;Tie2-Cre+/0) displayed enlarged white and brown adipocytes and lower UCP-1 expression.
NT3, mainly released by blood vessels, activates TrkC and regulates adipocyte differentiation and browning. Disruption of NT3/TrkC signaling conducts to hypertrophied white and brown adipocytes with reduced expression of the thermogenesis marker UCP-1.
To describe long-term survival and cardiovascular events in adult patients with single ventricle physiology (SVP) without Fontan palliation, focusing on predictors of mortality and comparing groups ...according to their cardiovascular physiology.
Multicentre observational and retrospective study including adult patients with SVP without Fontan palliation since their first adult clinic visit. The cohort was subdivided into 3 groups: Eisenmenger, restricted pulmonary flow, and aortopulmonary shunt. Death was considered as the main end point. Other clinical outcomes occurring during follow-up were considered as secondary end points.
A total of 146 patients, mean age 32.5 ± 11.1 years, were analysed. Over a mean follow-up of 7.3 ± 4.1 years, 33 patients (22.6%) died. Survival was 86% and 74% at 5 and 10 years, respectively. Right ventricular morphology was not associated with higher mortality. Four variables at baseline were related to a higher mortality: at least moderate atrioventricular valve regurgitation, platelet count < 150 × 103/mm3, GFR < 60 mL/min/1.73 m2, and QRS > 120 ms). A total of 34.2% of patients were admitted to the hospital due to heart failure, and 7.5% received a heart transplant. Other cardiovascular outcomes were also frequent: atrial arrhythmias in 19.2%, stroke in 15.1%, and pacemaker/implantable cardioverter-defibrillator in 6.2%/2.7%.
Adult patients with SVP who had not undergone Fontan exhibit a high mortality rate and frequent major cardiovascular events. At least moderate atrioventricular valve regurgitation, thrombocytopenia, renal dysfunction, and QRS duration > 120 ms at baseline visit allow identification of a cohort of patients at higher risk of mortality.
Décrire la survie à long terme et les événements cardiovasculaires chez les patients adultes présentant une physiologie à ventricule unique (PVU) sans intervention de Fontan, en se concentrant sur les prédicteurs de mortalité et en comparant les groupes en fonction de leur physiologie cardiovasculaire.
Étude observationnelle et rétrospective, multicentrique, incluant des patients adultes atteints de PVU sans intervention de Fontan depuis leur première visite en clinique adulte. La cohorte a été subdivisée en trois groupes : syndrome d'Eisenmenger, flux pulmonaire restreint ou fenêtre aorto-pulmonaire. Le décès a été considéré comme le critère principal d'évaluation. Les autres observations cliniques survenues au cours du suivi ont été considérées comme des critères secondaires.
Un total de 146 patients, d'un âge moyen de 32,5 ± 11,1 ans, a été considéré pour l’analyse. Sur un suivi moyen de 7,3 ± 4,1 ans, 33 patients (22,6 %) sont décédés. La survie était de 86 % et 74 % à 5 et 10 ans, respectivement. La morphologie du ventricule droit n'était pas associée à une mortalité plus élevée. Quatre variables initiales étaient liées à une mortalité plus élevée : régurgitation au moins modérée de la valve auriculo-ventriculaire, numération plaquettaire < 150 × 103/mm3, DFG < 60 ml/min/1,73 m2 et QRS > 120 ms). Au total, 34,2 % des patients ont été admis à l'hôpital en raison d'une insuffisance cardiaque, et 7,5 % ont reçu une transplantation cardiaque. D'autres conséquences cardiovasculaires étaient également fréquentes : arythmies auriculaires dans 19,2 % des cas, accident vasculaire cérébral dans 15,1 % des cas et stimulateur cardiaque/ défibrillateur cardioverteur implantable dans 6,2 % / 2,7 % des cas.
Les patients adultes atteints de PVU qui n'ont pas subi d'intervention de Fontan présentent un taux de mortalité élevé et des événements cardiovasculaires majeurs fréquents. Une régurgitation au moins modérée de la valve auriculo-ventriculaire, une thrombocytopénie, une dysfonction rénale et une durée du QRS > 120 ms lors de la visite initiale permettent de distinguer une cohorte de patients présentant un risque de mortalité plus élevé.
Human leukocyte antigen (HLA) study in Murcian individuals was performed in order to provide information of their historical origins and relationships with other Iberian and Mediterranean ...populations. HLA class I and class II alleles were determined in 173 unrelated Caucasoid donors from Murcia Region in the Southeast of Spain by serologic and DNA based polymerase chain reaction (PCR) typing. Class I antigen and class II allele frequencies of our series were not very different to those found in Spaniards. The analysis of extended haplotypes showed that the three haplotypes most frequent in our population were respectively, A29-B44-Cwb-DRB1*0701-DRB4*0101-DQA1*0201-DQB1*0202, A1-B8-Cw7-DRB1*0301-DRB3*0101-DQA1*0501-DQB1*0201 and A30-B18-Cw5-DRB1*0301-DRB3*0101-DQA1*0501-DQB1*0201. They were followed by A26-B38-Cwb-DRB1*1301-DRB3*0202-DQA1*0103-DQB1*0603, which could point to an ancestral relationship between Murcian and Portuguese Iberian populations, and by A2-B7-Cw7-DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 also present in all Iberian Peninsula populations. Allelic frequencies, populations distance dendrogram and correspondence analysis were used to study the relationships between Murcian and other populations. The closest relation was observed with Spaniards and Portuguese, followed in decreasing order by French, Italians, Algerians, Germans, Catalans, Basques, Cretans, Sardinians, and Greeks. Thus, Murcian population seems to belong to the European genetic pool, revealing a lesser genetic distance with the North Africans and the rest of populations from the Iberian Peninsula.
Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) ligands and regulate functions of natural killer cells and subsets of T cells. KIR/HLA-I interactions ...allow predicting natural killer cell alloreactivity in hematopoietic stem cell transplantation and in HLA-compatible kidney transplants, but its meaning in liver transplantation remains controversial.
KIR and HLA genotypes were studied in 402 liver transplants, using sequence-specific oligonucleotides and primer methods. Recipients and donor KIRs, HLA-C genotypes, KIR gene mismatches (MMs) between recipient-donor pairs, and KIR/HLA-ligand combinations were analyzed in overall transplantations, in the acute rejection (AR; n=110) and non-AR (n=292) groups.
KIR gene MMs between recipients and donors, mainly in activating KIRs, and KIR2DL3 and KIR2DS1 of recipients in the presence of donor C2 ligands, significantly enhanced early AR rate (P<0.05), with KIR2DL3 and KIR2DS1 exhibiting a synergic effect in dependence of the donor C2 ligand number (χ2=7.662, P=0.022). KIR2DL3, KIR2DS1, and also KIR2DS4 significantly influenced short-term graft survival, with a benefit for transplantations combining KIR2DL3 recipients and donors having C1 ligands (log rank, P<0.019 at 1 year; hazards ratio HR, 0.321; 95% confidence interval CI, 0.107-0.962; P=0.042), whereas KIR2DS1 and KIR2DS4 recipients combined with donors lacking C1 ligands (C2/C2) exhibited a worse graft survival (log rank, P=0.035 at 6 months; HR, 7.713; 95% CI, 2.156-27.369; P=0.002 for KIR2DS1; and log rank, P=0.006 at 1 year; HR, 3.794; 95% CI, 1.267-11.365; P=0.017 for KIR2DS4).
This study shows that KIR gene-gene MMs increase AR and that KIRs/C ligands associated to AR and KIR2DS4/C ligands also influence short-term graft survival.
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