Cytolytic CD8+ T lymphocytes are the main cell type involved in the fatal lymphoproliferative-accelerated phase of the Chediak-Higashi syndrome (CHS). To generate a cellular tool to study the defects ...of this T cell subset in vitro, we have used Herpesvirus saimiri, a lymphotropic virus that transforms human T lymphocytes into extended growth and in addition, endows them with natural killer (NK) features. Transformed CHS CD8+ T cells were generated and characterized in comparison with healthy controls. The results showed that transformed CHS T cells maintained the defects described in primary CHS lymphocytes, such as giant secretory lysosomes and impaired NK and T cell receptor/CD3-induced, perforin-mediated cytolytic activity which, however, could be restored after extended culture in the presence of interleukin-2 (IL-2). Upon activation with phorbol ester plus calcium ionophore or upon extended culture with IL-2, transformed CHS T cells showed normal, perforin-independent plasma membrane CD178/CD95L/FasL-mediated cytolytic activity but negligible secretion of microvesicle-bound CD95L. Transformed (and primary) CHS T cells were otherwise normal for cytolysis-independent activation functions, such as proliferation, surface expression of several activation markers including major histocompatibility complex class II, and cytokine or surface activation-marker induction. Therefore, the CHS protein CHS1/LYST (for lysosomal traffic regulator) can be dispensable for certain NK and T cell cytolytic activities of activated CHS CD8+ T lymphocytes, but it seems to be required for microvesicle secretion of CD95L. We conclude that transformed CHS T cells may be useful as a tool to study in vitro the relative role of CHS1/LYST in NK and T lymphocyte cytolysis and antigen presentation.
In this study, we present an 18-month serological follow-up of 294 patients with COVID-19 pneumonia. The aim was to assess the dynamics of serological response and its correlation with clinical ...worsening, as well as to describe clinical worsening determinants. Results of the study showed an early immunoglobulin M response, which clearly diminished starting at 4 months, but nonetheless, a small group of patients remained positive. As for immunoglobulin G, levels were higher up to 6 months in patients who presented clinical worsening during hospitalization. High titers of the immunoglobulin were maintained in all patients during follow-up, which would indicate that humoral immunity due to infection is long-lasting. Male sex, presence of myalgias and extensive radiological affectation were significantly correlated with clinical worsening.
Gambling disorder in youth is an emerging public health problem, with adolescents and young adults constituting a vulnerable age group for the development of gambling-related problems. Although ...research has been conducted on the risk factors for gambling disorder, very few rigorous studies can be found on the efficacy of preventive interventions in young people. The aim of this study was to provide best practice recommendations for the prevention of disordered gambling in adolescents and young adults. We reviewed and synthesized the results of existing RCTs and quasi-experimental studies covering nonpharmacological prevention programs for gambling disorder in young adults and adolescents. We applied the PRISMA 2020 statement and guidelines to identify 1483 studies, of which 32 were included in the systematic review. All studies targeted the educational setting, i.e., high school and university students. Most studies followed a universal prevention strategy, that particularly targeted adolescents, and an indicated prevention strategy for university students. The reviewed gambling prevention programs generally showed good results in terms of reducing the frequency and severity of gambling, and also regarding cognitive variables, such as misconceptions, fallacies, knowledge, and attitudes towards gambling. Finally, we highlight the need to develop more comprehensive prevention programs that incorporate rigorous methodological and assessment procedures before they are widely implemented and disseminated.
In some tissues, rapid effects of estrogens have been described at the plasma membrane level including activation of the MAPK activity. In rat adipocytes, the present study demonstrates that ...physiological concentrations (0.1–10 nm) of E2 rapidly activate the p42/p44 MAPK. This effect was blocked by the pure estrogen antagonist, ICI 182 780, and appeared specific for E2 because 17α-E2, T, and progesterone failed to change the MAPK activity. Pertussis toxin; PP2, a selective inhibitor of Src family kinase; and wortmannin all reduced the magnitude of MAPK activation by E2 suggesting involvement of the Gi-protein/Src family kinase/PI3K pathway. Classical PKCs and MAPK kinase were also involved in MAPK activation by E2. Interestingly, this activation was observed in late but not early differentiated rat preadipocytes, and the immunoreactive ERα protein was detected only in adipocyte membrane, suggesting that the adipocyte membrane structure is required for the nongenomic effect of E2. Moreover, E2 induced a rapid nuclear translocation of MAPK together with a fast MAPK- dependent activation of cAMP response element binding protein leading to a transcriptional activation of cAMP response element binding protein-responsive genes and reported plasmids. However, the E2 increase in adipocyte activator protein-1 DNA binding does not seem to be fully explained by the E2 activation of the MAPK pathway. This study provides clear evidence for an additional nongenomic mechanism whereby estrogens may exert their control on adipose tissue metabolism.
The progressive ageing of the population is leading to an increase in multimorbidity and polypharmacy, which in turn may increase the risk of hospitalization and mortality. The enhancement of care ...with information and communications technology (ICT) can facilitate the use of prescription evaluation tools and support system for decision-making (DSS) with the potential of optimizing the healthcare delivery process.
To assess the effectiveness and cost-effectiveness of the complex intervention MULTIPAP Plus, compared to usual care, in improving prescriptions for young-old patients (65-74 years old) with multimorbidity and polypharmacy in primary care.
This is a pragmatic cluster-randomized clinical trial with a follow-up of 18 months in health centres of the Spanish National Health System. Unit of randomization: family physician. Unit of analysis: patient.
Patients aged 65-74 years with multimorbidity (≥ 3 chronic diseases) and polypharmacy (≥ 5 drugs) during the previous 3 months were included.
n = 1148 patients (574 per study arm).
Complex intervention based on the ARIADNE principles with three components: (1) family physician (FP) training, (2) FP-patient interview, and (3) decision-making support system.
The primary outcome is a composite endpoint of hospital admission or death during the observation period measured as a binary outcome, and the secondary outcomes are number of hospital admission, all-cause mortality, use of health services, quality of life (EQ-5D-5L), functionality (WHODAS), falls, hip fractures, prescriptions and adherence to treatment. Clinical and sociodemographic factors will be explanatory variables.
The main result is the difference in percentages in the final composite endpoint variable at 18 months, with its corresponding 95% CI. Adjustments by the main confounding and prognostic factors will be performed through a multilevel analysis. All analyses will be carried out in accordance to the intention-to-treat principle.
It is important to prevent the cascade of negative health and health care impacts attributable to the multimorbidity-polypharmacy binomial. ICT-enhanced routine clinical practice could improve the prescription process in patient care.
ClinicalTrials.gov NCT04147130 . Registered on 22 October 2019.
This study evaluated the impact of heptavalent pneumococcal conjugate vaccine (HPCV) on invasive pneumococcal disease (IPD) in children aged ≤ 5 years in Barcelona, Spain. The incidence of IPD, ...vaccine uptake and prevalence of nasopharyngeal colonisation were analysed in two different periods: 1999–2001 (pre-licence period), and 2002–2004 (post-licence period). In total, 121 cases of IPD were identified. The overall incidence of IPD decreased from 96.9 cases/100 000 to 90.6 cases/100 000 (OR 0.93, 95% CI 0.69–1.26, p 0.71) between the two periods. The proportion of cases caused by non-vaccine-related serotypes (NVS) increased from 21% to 43.7% (OR 2.9, 95% CI 1.2–7, p 0.01). IPD was diagnosed in seven vaccinated children, six of whom were infected by NVS. There was a trend of diminishing prevalence of resistance to penicillin and macrolides in 2002–2004. The incidence of empyema increased from 1.7 to 8.5/100 000 (OR 4.5, 95% CI 0.91–18, p 0.06). The rate of vaccination ranged from 4.8% to 34%. It was concluded that the rates of IPD in this area did not decrease following the introduction of HPCV. The low uptake of vaccine and the greater proportion of colonisation/infection by NVS probably explain these findings. A trend of increasing empyema was also apparent. A decrease in the prevalence of penicillin and macrolide resistance paralleled the progressive uptake of vaccine.
Among young children, pneumococcal nasopharyngeal colonization (NPC) rates of >90% have been described. The aim of our study was to assess the effect of amoxicillin exposure on the NPC. From Dec 2001 ...to Feb 2004, less than 5 years old children with respiratory symptoms and fever who were prescribed amoxicillin were eligible. Three nasopharyngeal swabs were taken: at the time of the initial visit (IV), 60 hours after amoxicillin discontinuation (end of treatment visit, ETV), and 4 weeks later (follow-up visit, FUV). One hundred and thirty four children were included. NPC was detected in 58.5%, 42.9% and 51% of <1, 1-2 and >2 years-old children respectively (NS). Vaccine serotypes (VS) or vaccine-related serotypes (VRS) were identified in 80%, 40% and 55% of <1-year-old, 1-2 year-old and >2-year-old children respectively (NS). The proportion of PNSSP was 60% in <1-year-old children, 43% in 1-2 year-old children and 40% in >2-year-old children (NS). 49 out of 134 (36.5%) children completed the three study visits. 51%, 22.4% and 46.9% of those were colonized at IV, ETV and FUV, respectively (p=0.007). The percentage of resistant SP was 28%, 45.5% and 8.7% (p=0.05) for penicillin. In children <1 year of age, a higher proportion of SP colonization, presence of VS and PNSSP was found. A downfall of NPC at the end of therapy was observed. NPC returned to baseline levels thanks to "de novo" colonization in half of the cases, a few weeks after.
In order to elucidate the molecular mechanisms whereby ovarian
hormones, and particularly estrogens, modulate fat cell metabolism, we
investigated the effects of estradiol administration on
c-fos and ...c-jun expressions in fat cells
from ovariectomized (OVX) rats. Estradiol treatment resulted in a rapid
increase in c-fos and c-jun messenger RNA
(mRNA) and protein levels (about 2-fold). These effects of estradiol on
c-fos and c-jun mRNAs were blocked by
actinomycin D but not by cycloheximide treatment, suggesting that
estradiol modulates c-fos and c-jun
transcription. Moreover, the estradiol-induction of both transcripts
was partially suppressed by the estrogen-receptor antagonist ICI
182,780. In contrast, progesterone administration did not affect
c-fos and c-jun mRNA levels indicating a
hormonal specificity of estrogen action. However, an antagonism of
estradiol-induction of both genes was observed after progesterone
treatment. In addition, the estradiol-induced changes in
c-fos and c-jun mRNA expressions could
not be observed in castrated males suggesting a gender-specific effect
of estradiol. Finally, in OVX rats, estradiol treatment stimulated the
specific AP-1 DNA binding activity (about 5-fold) in adipocyte nuclear
extracts as assessed by electrophoretic mobility shift assays. These
results suggest that some of the estrogen effects in fat cells from
female rats are mediated through induction of the AP-1 complex
expression and consequently through modulation of the AP-1 dependent
gene expression in adipocytes.
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