Interaction of ACEI antihypertensive agent's administration with the inflammatory status at admission concerning COVID-19 clinical stay outcomes.

Interactions between anti-hypertensive agents (ACEI), comorbidities, inflammation, and stress status may impact hospital stay duration in COVID-19 patients. This retrospective study analyzed epidemiological data, comorbidities, metabolic/inflammatory markers, and clinical information from 165 SARS-CoV-2 positive patients. In a multiple linear regression model, an IL-6 higher than 100 mg/L, glucose at admission (baseline levels at the hospital entry), and the interaction between ACEI administration and LDH predicted the days of hospital admission (P < 0.001). In conclusion, hypertensive patients suffering more severe inflammatory condition assessed by LDH levels clinically benefited more and reduced the hospital stay when prescribed ACEI agents than those with lower systemic baseline inflammation at admission.

Real-Life Impact of Glucocorticoid Treatment in COVID-19 Mortality: A Multicenter Retrospective Study.

We aimed to determine the impact of steroid use in COVID-19 in-hospital mortality, in a retrospective cohort study of the SEMICOVID19 database of admitted patients with SARS-CoV-2 laboratory-confirmed pneumonia from 131 Spanish hospitals. Patients treated with corticosteroids were compared to patients not treated with corticosteroids; and adjusted using a propensity-score for steroid treatment. From March-July 2020, 5.262 (35.26%) were treated with corticosteroids and 9.659 (64.73%) were not. In-hospital mortality overall was 20.50%; it was higher in patients treated with corticosteroids than in controls (28.5% versus 16.2%, OR 2.068 [95% confidence interval; 1.908 to 2.242]; p = 0.0001); however, when adjusting by occurrence of ARDS, mortality was significantly lower in the steroid group (43.4% versus 57.6%; OR 0.564 [95% confidence interval; 0.503 to 0.633]; p = 0.0001). Moreover, the greater the respiratory failure, the greater the impact on mortality of the steroid treatment. When adjusting these results including the propensity score as a covariate, in-hospital mortality remained significantly lower in the steroid group (OR 0.774 [0.660 to 0.907], p = 0.002). Steroid treatment reduced mortality by 24% relative to no steroid treatment (RRR 0.24). These results support the use of glucocorticoids in COVID-19 in this subgroup of patients.

Exploring Host Genetic Polymorphisms Involved in SARS-CoV Infection Outcomes: Implications for Personalized Medicine in COVID-19.

OBJECTIVE: To systematically explore genetic polymorphisms associated with the clinical outcomes in SARS-CoV infection in humans. METHODS: This comprehensive literature search comprised available English papers published in PubMed/Medline and SCOPUS databases following the PRISMA-P guidelines and PICO/AXIS criteria. RESULTS: Twenty-nine polymorphisms located in 21 genes were identified as associated with SARS-CoV susceptibility/resistance, disease severity, and clinical outcomes predominantly in Asian populations. Thus, genes implicated in key pathophysiological processes such as the mechanisms related to the entry of the virus into the cell and the antiviral immune/inflammatory responses were identified. CONCLUSIONS: Although caution must be taken, the results of this systematic review suggest that multiple genetic polymorphisms are associated with SARS-CoV infection features by affecting virus pathogenesis and host immune response, which could have important applications for the study and understanding of genetics in SARS-CoV-2/COVID-19 and for personalized translational clinical practice depending on the population studied and associated environments.

Nutrition education in medical schools (NEMS). An ESPEN position paper.

BACKGROUND & AIMS: Nutrition education is necessary in the training of healthcare professionals, including medical students. However, recent surveys showed that there is a high variability within Medical Schools in different countries. The aim of this ESPEN position paper is to identify a minimum curriculum knowledge in nutrition that serves to improve the training of the future doctors and how to solve the main barriers of its implementation in university centres. METHODS: In 2017, the ESPEN Executive Committee launched the Nutrition Education in Medical Schools (NEMS) Project and formed a core working group including members of the ESPEN Nutrition Education Study Group (NESG) and representatives of several European Medical Schools. This group met in Brussels, on 19th July 2018 and decided to prepare a position paper on this topic. RESULTS: Five main learning objectives and twenty-one topics on human nutrition, within its three domains (basic, applied and clinical nutrition) were identified to be fulfilled at the end of training in all Medical Schools. The experts showed the following key factors for its implementation: establish a nutrition curriculum committee, use different models of integration of the contents in the curriculum (vertical and horizontal), have a multidisciplinary and experienced faculty, incorporate a variety of teaching models, and evaluate the programme periodically. CONCLUSIONS: Nutrition Education is necessary and should be mandatory in all Medical Schools. This position paper aims at improving this gap knowledge and gives some clues for a successful implementation of the changes in the medical curriculum at university centres.

Genotypic distribution of common variants of endosomal toll like receptors in healthy Spanish women. A comparative study with other populations.

Genetic variants of endosomal toll like receptors (TLR) have been associated with many infectious, autoimmune and inflammatory diseases, but few studies have been reported in the Spanish population. The aim of this study was to describe the allelic and genotypic distributions of some common nucleotide substitutions of endosomal TLRs in healthy Spanish women and to compare them with those already published in other population groups. Nine substitutions were analysed in 150 DNA samples from 150 Spanish, non-related healthy females: TLR3 rs3775291 and rs5743305; TLR7 rs179008 and rs5743781; TLR8 rs3764880 and TLR9 rs187084, rs5743836, rs352139 and rs352140. Genotyping was carried out by real time PCR and melting curve analysis in a LightCycler 480. A systematic review was performed in order to compare the genotypic distributions in our cohort with those previously published in other population groups. The comparative study was performed with the two tailed Fisher's test or the Yates continuity correction for the Chi-square test when appropriate. No homozygotes for rs5743781 in TLR7 were found, and rs352139 and rs352140 of TLR9 were in strong linkage disequilibrium. Genotype distributions in endosomal TLR are similar to other Spanish series previously reported. As expected, most differences were found when comparing our distributions with Asiatics, but differences were also found with other Caucasian populations. Since there are significant variations in genotypic distributions of TLRs in both interracial groups and within the same ethnic group, to carry out studies of disease susceptibility in more restricted groups is mandatory.

Apoptosis and acute cellular rejection in human heart transplants.

INTRODUCTION AND OBJECTIVES: Apoptosis has been implicated in the pathophysiology of various forms of heart disease. Acute cellular rejection leads to morbidity after heart transplantation and invasive techniques are needed for its diagnosis. We investigated the presence of cardiomyocyte apoptosis in transplanted hearts, its progression, its relationship with rejection, and the possibility that serological markers of apoptosis can be used to detect rejection noninvasively. METHODS: Overall, 130 endomyocardial biopsies obtained sequentially from 14 consecutive patients during the first 6 months following heart transplantation underwent histochemical analysis. The degree of acute rejection was determined, myocyte apoptosis was assessed using the TUNEL method, and caspase-3 activity was measured. In the first 10 patients, soluble Fas, tumor necrosis factor-alpha (TNFα) and interleukin 6 levels were determined in serum collected at biopsy. RESULTS: Apoptotic cells were detected in 81.5% of biopsies. No significant correlation was found between the apoptotic index and either the degree of rejection or the time from transplantation; there was only a trend to higher values during prolonged episodes of rejection, which did not reach statistical significance. An inverse correlation was observed between the degree of rejection and the TNFα level (rs=-0.33; P=.003). There was no correlation with any other variable. CONCLUSIONS: Cardiomyocyte loss due to apoptosis was observed in transplanted hearts, but no correlation was observed with either acute rejection or the time from transplantation. Our findings suggest there could be an inverse correlation between rejection and the serum TNFα level. No serum parameter evaluated was regarded as suitable for the noninvasive diagnosis of acute rejection.

Drug induction apoptosis assay as predictive value of chemotherapy response in patients with B-cell chronic lymphocytic leukemia.

A large number of prognostic factors are available to help predict the course of the disease for patients with B-cell chronic lymphocytic leukemia (B-CLL). However, it is not clear the involvement of these well established prognostic factors in the clinical response of the patients with B-CLL to the chemotherapy. The possible association of the patient clinical-biological characteristics and the in vitro response to chemotherapic agents may serve to provide powerful predictive information to identify optimum treatment for patients. An apoptosis induction assay displays the patient in vitro responses to chemotherapy and the possible association with their clinical-biological characteristics. In this study, patients showed a significant better in vitro response to drugs when they were in the initial stages of the disease or with low beta(2) microglobulin serum level. Response to purine analogues was significantly higher in patients with long lymphocyte doubling time (LDT), few cells expressing CD38, normal karyotype or no p53 deletion, whereas there was no correspondence with ZAP-70 expression. Furthermore, a good correlation was shown between in vitro apoptosis induction assay and the patient clinical response to purine analogues. In conclusion, association between in vitro drug sensitivity and some of the markers considered as prognostic factors could help to develop personalised therapeutic regimens for patients with B-CLL.

Monocytes and T lymphocytes contribute to a predominance of interleukin 6 and interleukin 10 in systemic lupus erythematosus.

OBJECTIVE: To investigate the contribution of T lymphocytes and monocytes to cytokine production in systemic lupus erythematosus (SLE). METHODS: Forty-five SLE patients and 19 healthy volunteers were included. Serum levels of tumor necrosis factor alpha (TNFalpha), interferon gamma (IFN gamma), interleukin (IL)-6, and IL10 were quantified by ELISA. The cytokine production capacities of peripheral blood mononuclear cells were assessed by culturing in vitro with PMA+Ionomycin or LPS. The intracellular cytokine expression was measured by flow cytometry in T lymphocytes and monocytes, respectively. The influence of the disease activity (measured as the SLE-disease activity index; SLEDAI) and the treatment the patients were receiving was evaluated. RESULTS: Serum IL10, IL6, and TNFalpha levels were increased in patients (P

Analysis of competing risks of causes of death and their variation over different time periods in Hodgkin's disease.

PURPOSE: Hodgkin's disease is considered a model of curable illness. However, long-term studies show excessive mortality in relation to the general population. We studied the various causes of death by use of competing risks and their evolution over the years. EXPERIMENTAL DESIGN: All patients diagnosed with Hodgkin's disease at our institution between 1967 and 2003 were included. The competing risks of causes of death and their vital situation were examined in three time periods: cohort A with patients treated before 1980, cohort B with patients treated from 1981 to 1986, and cohort C with patients treated from 1986 onwards. RESULTS: We studied 534 patients, with a median follow-up time of 9.1 years for the whole cohort. The 5-year, 15-year, and 20-year Kaplan-Meier survival estimates for all patients were 81%, 72%, and 65%, respectively. At the close of the study, 337 (63.1%) were alive and 170 (31.8%) patients had died. The most common cause of death was the progression of Hodgkin's disease, followed by deaths due to a second tumor. Survival was significantly worse in the first period than in the other two (P < 0.001), and in the three periods, the main cause of death was tumor progression. CONCLUSIONS: The progression of Hodgkin's disease is the main cause of death. Over time, a reduction in death related to infection and the acute toxicity of treatment was seen. A lot of patients still die for reasons linked to delayed side effects of radiotherapy, such as second tumors and heart disease, which is important to plan preventive activities and clinical research.

Association of the microsatellite in the 3' untranslated region of the CD154 gene with rheumatoid arthritis in females from a Spanish cohort: a case-control study.

CD40-CD154 interaction is an important mediator of inflammation and has been implicated in T helper type 1-mediated autoimmune diseases including rheumatoid arthritis (RA). Linkage studies have shown association of markers in the proximity of the CD154 gene. In the present work we investigated whether specific allele variants of the microsatellite in the 3' UTR of the CD154 gene might modulate the risk of RA. The study, in a case-control setting, included 189 patients and 150 healthy controls from the Canary Islands, Spain. The 24CAs allele was less represented in female patients than in controls (0.444 in controls versus 0.307 in patients, P = 0.006, odds ratio (OR) 0.556, 95% confidence interval (CI) 0.372 to 0.831) but not in males (0.414 versus 0.408), and only when homozygous (P = 0.012; OR 0.35, 95% CI 0.16 to 0.77). We also verified that CD154 association with RA was independent of human leukocyte antigen (HLA) phenotype. A further functional study showed that after stimulation anti-CD3, CD154 mRNA was more stable in CD4+ T lymphocytes from patients with RA bearing the 24CAs allele (mRNA half-life 208 minutes) than in patients without the 24CAs allele (109 minutes, P = 0.009). However, a lower percentage of CD154+CD4+ T lymphocytes was seen in freshly isolated peripheral blood mononuclear cells from patients carrying 24CAs alleles (mean 4.28 versus 8.12; P = 0.033), and also in CD4+ T lymphocytes stimulated with anti-CD3 (median 29.40 versus 47.60; P = 0.025). These results were concordant with the smaller amounts of CD154 mRNA isolated from stimulated T lymphocytes with 24CAs alleles. The CD154 microsatellite therefore seems to affect the expression of the gene in a complex manner that implies not only mRNA stability. These data suggest that the CD154 microsatellite contributes to the regulation of mRNA and protein expression, although further studies will be necessary to elucidate its role in disease predisposition.

CD5 does not regulate the signaling triggered through BCR in B cells from a subset of B-CLL patients.

CD5 is a transmembrane protein expressed on all T lineage cells and a subset of B cells. It is known that CD5 is physically associated with the T-cell receptor and B-cell receptor (BCR), inhibiting the signaling triggered by both of them. CD5 is also characteristic of B-chronic lymphocytic leukemia (B-CLL) B cells, although its implication in the development of this lymphoproliferative disorder has not been studied. In the present study, we examined the effect of CD5 in apoptosis, cell viability and global protein tyrosine phosphorylation mediated by BCR in B cells from B-CLL patients. As opposed to tonsil B cells, we did not observe an increase in the apoptotic or viability signals induced by anti-immunoglobulin M or SAC/interleukin-2 when CD5 was dissociated from BCR in leukemic cells of the majority of patients. We also observed that CD5 did not regulate the BCR-induced phosphotyrosine pattern in B-CLL B cells. These findings suggest that CD5 does not inhibit properly the BCR-mediated signaling in leukemic cells. This defect in inhibiting the BCR might contribute to the enhanced survival of B-CLL B cells.

CD5 provides viability signals to B cells from a subset of B-CLL patients by a mechanism that involves PKC.

B-chronic lymphocytic leukaemia (B-CLL) is a heterogeneous disease characterized by an accumulation of B lymphocytes expressing CD5. To date, the biological significance of this molecule in B-CLL B cells remains to be elucidated. In this study, we have analysed the functional consequences of the binding of an anti-CD5 antibody on B-CLL B cells. To this purpose, we have measured the percentage of viability of B-CLL B cells in the presence or in the absence of anti-CD5 antibodies and also examined some of the biochemical events downstream the CD5-signalling. We demonstrate that anti-CD5 induces phosphorylation of protein tyrosine kinases and protein kinase C (PKC), while no activation of Akt/PKB and MAPKs is detected. This signalling cascade results in viability in a group of patients in which we observe an increase of Mcl-1 levels, whereas the levels of bcl-2, bcl-x(L) and XIAP do not change. We also report that this pathway leads to IL-10 production, an immunoregulatory cytokine that might act as an autocrine growth factor for leukaemic B cells. Inhibition of PKC prevents the induction of Mcl-1 and IL-10, suggesting that the activation of PKC plays an important role in the CD5-mediated survival signals in B cells from a subset of B-CLL patients.

Prognostic value of neutrophils and NK cells in bronchoalveolar lavage of sarcoidosis.

BACKGROUND: Not all the patients with sarcoidosis need pharmacological therapy, and the decision to start therapy is based mainly on clinical conditions. The aim of this study was to evaluate the prognostic value of the leukocyte and lymphocyte subpopulations in the bronchoalveolar lavage fluid from these patients. METHODS: Thirty-three nonsmoking patients with sarcoidosis were included and classified based on the presence of Löfgren's syndrome (n = 11), the radiological stage (12 at Stage I, 17 at Stage II, and 4 at Stage III), and their follow-up. Differential leukocyte subsets and the lymphocyte subpopulations were determined by flow cytometry. RESULTS: The percentage of neutrophils was lower in patients with Löfgren's syndrome (P = 0.038) and in patients at Stage I (P = 0.002). Patients with a poor outcome had a higher percentage of neutrophils (P = 0.004) and NK cells (P = 0.023) than those with a stable disease. Finally, a higher percentage of NK cells was found in those patients who needed a steroid treatment (P = 0.012). CONCLUSIONS: Increased percentages of neutrophils and NK cells in the bronchoalveolar lavage fluid from patients with sarcoidosis are associated with a poor outcome and a higher probability to need steroids treatment. The percentage of neutrophils was also lower in patients with Löfgren's syndrome.

[Clinical value of the ankle-brachial index in patients at risk of cardiovascular disease but without known atherothrombotic disease: VITAMIN study]. / Valor de la determinación del índice tobillo-brazo en pacientes de riesgo vascular sin enfermedad aterotrombótica conocida: estudio VITAMIN.

INTRODUCTION AND OBJECTIVES: Detecting peripheral arterial disease by measuring the ankle-brachial index can help identify asymptomatic patients with established disease. We investigated the prevalence of peripheral arterial disease (i.e., an ankle-brachial index <0.9) and its potential clinical and therapeutic impact in patients with no known arterial disease who were seen at internal medicine departments. METHODS: This multicenter, cross-sectional, observational study included patients at risk of cardiovascular disease who were selected on the basis of age, gender and the presence of conventional risk factors. No patient was known to have arterial disease. RESULTS: The study included 493 patients, 174 (35%) of whom had diabetes, while 321 (65%) did not. Only 16% were in a low-risk category according to their Framingham score. An ankle-brachial index <0.9 was observed in 27.4%, comprising 37.9% of those with diabetes and 21.3% of those without. Multiple logistic regression analysis showed that the risk factors associated with an ankle-brachial index <0.9 were age, diabetes, and hypercholesterolemia. There was a significant relationship between the ankle-brachial index and Framingham risk categories. Therapeutically, only 21% of patients with an ankle brachial index <0.9 were taking antiplatelet drugs. Overall, 20% had a low-density lipoprotein cholesterol concentration <100 mg/dl and 52% had a concentration <130 mg/dl. Some 42% had arterial blood pressures below 140/90 mm Hg. CONCLUSIONS: Asymptomatic peripheral arterial disease was detected in a high proportion of patients with an intermediate or high cardiovascular disease risk. The ankle-brachial index should be measured routinely in patients at risk of cardiovascular disease who are seen at internal medicine departments.

Polymorphism in the CD5 gene promoter in B-cell chronic lymphocytic leukemia and mantle cell lymphoma.

Despite the low incidence of microsatellite instability (MSI) in lymphoid malignant neoplasms, it has been reported that the CD5 promoter MSI was relatively frequent among B-cell chronic lymphoproliferative disorders. We studied the presence of MSI in the CD5 promoter in 134 cases of B-cell chronic lymphocytic leukemia (B-CLL) and 47 of mantle cell lymphoma (MCL) by comparing the pattern of microsatellite repeats on autologous germline and tumor DNA samples. Microsatellite alterations were not observed in any case. However, the allele distribution of this polymorphism showed a higher frequency of the 18 CA allele (0.585) in MCL cases (P = .026; odds ratio [OR], 1.75; 95% confidence interval [CI], 1.07-2.87) and of the 19 CA allele (0.179) in B-CLL cases (P = .005; OR, 2.26; 95% CI, 1.27-4.01) compared with control cases (0.442 and 0.087, respectively). This suggests that although MSI seems not to be involved in the pathogenesis of these 2 lymphoid malignant neoplasms, the polymorphic CD5 promoter is associated with increased susceptibility to these disorders.